Background of the Invention
[0001] The present invention relates to naphthalene derivatives, to processes and intermediates
for their preparation, to pharmaceutical compositions containing them and to their
medicinal use. The compounds of the present invention are selective agonists and antagonists
of serotonin 1 (5-HT
1) receptors and as such are useful in treating migraine and other disorders for which
a 5-HT
1 agonist or antagonist is indicated.
[0002] European patent application 434,561-A describes 7-alkyl, alkoxy, and hydroxy substituted-1-(4-substituted-1-piperazinyl)-naphthalenes.
The compounds are claimed to be 5-HT
1 agonists and antagonists useful for the treatment of migraine, depression, anxiety,
schizophrenia, stress and pain. However, EP 434,561-A neither discloses nor suggests
the type of 7-substituted 1-(1-piperazinyl)-naphthalenes provided by the present invention.
[0003] European patentapplication 343,050-A1 describes 7-unsubstituted, halogenated, and
methoxy substituted-1-(4-substituted-1-piperazinyl)-naphthalenes as 5-HT
1A ligands useful in therapy. However, EP 343,050-A1 neither discloses nor suggests
the type of 7-substituted 1-(1-piperazinyl)-naphthalenes provided by the present invention.
[0004] Drug Res. Dev., 1991, 22, 25 describes 7-methoxy-1-(1-piperazinyl)-naphthalene as
a 5-HT
1 ligand. This publication neither discloses nor suggests the type of 7-substituted
1-(1-piperazinyl)-naphthalenes provided by the present invention.
[0005] Thus ligands with high affinity for the 5-HT
1 receptors are well recognized as having therapeutic value for the treatment of human
conditions caused by serotonin imbalance.
Summary of the Invention
[0006] The present invention relates to compounds of the formula
where
R1 is of the formulae
R2 is -R4, -O-R4, -O-S(O)2-R4, -NR4R5, R4-(CH2)b-NH(C=X)-(CH2)c-, R4-(CH2)b-O(C=O)NH-(CH2)c-(C=O)NH-, R4-(C = O)NH-(C=O)NH-, -(CH2)b-NH(C=X)-(CH2)c-R4, R4-(CH2)b-O(C=O)-(CH2)c-, -(CH2)b-O(C=O)-(CH2)c-R4, -NH(C=X)NH-R4, R4-O(C=O)O-, -O(C = O)NH-R4, R4-O(C=O)NH-, -(CH2)b-(C=O)-(CH2)c-R4, -NH-S(O)2-R4, -C(OH)R4R5, -CH(OH)-R4, -(C=O)-NR4R5, -CN, -NO2, substituted C1 to C6 alkyl, substituted or unsubstituted C1 to C6 alkenyl, or substituted or unsubstituted C1 to C6 alkynyl, said substituted moieties substituted with a moiety of the formulae -R4, -R4R5, -O-R4, or -S(O)d-R4;
R3 is hydrogen, CH3OCH2CH2, C1 to C6 alkyl, C1 to C6 alkylaryl, or aryl;
R4 and R5 are each independently
hydrogen, C1 to C6 alkyl, C1 to C6 alkylaryl, with the proviso that, when R2 is -R4 or -OR4, R4 is not hydrogen or C1 to C6 alkyl;
R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, and R18 are each independently H, halogen, -CF3, -(C=O)R20, -CN, -OR20, -NR20R21, -NR20SO2R22, -NR20CO2R22, -N=CH-N(CH3)2, -S(O).R20. -SO2NR20R21, -NO2, aryl, C1 to C6 alkylaryl, -(C=O)OR20, -(C=O)NR20R21, C1 to C6 alkyl, C1 to C6 alkenyl, and C1 to C6 alkynyl;
R6 and R7, R7 and R8, R8 and R9, R9 and R10, R11 and R12, R12 and R13, R13 and R14, R15 and R16, R16 and R17, and R17 and R18 may be taken together to form a five-to-seven-membered alkyl ring, a six-membered
aryl ring, a five to seven membered heteroalkyl ring having one heteroatom of N, O,
or S, or a five-to six-membered heteroaryl ring have 1 or 2 heteroatoms of N, O, or
S;
R19 is hydrogen or C1 to C3 alkyl;
R20 and R21 are each independently hydrogen, C1 to C6 alkyl, aryl, or C1 to C6 alkylaryl, or may be taken together to form a C4 to C7 alkyl ring;
R22 is C1 to C6 alkyl, aryl, or C1 to C6 alkylaryl;
A, B, D, E, and F are each independently C, N, or (C=O);
G, I, J, and K are each independently C, N, O, S, or (C=O), with the proviso that
there is at most one of O, (C=O), or S per ring;
L and Z are each independently C or N;
M is C, N, or (C―O);
X is O or S;
a is 0, 1 or 2;
e is 0, 1 or 2;
d is 0, 1, or 2;
b and c are each independently 0, 1, 2, 3, 4, 5, or 6, with b+c being at most 6;
a broken line indicates the presence optionally of a bond and the above aryl groups
and the aryl moieties of the above alkylaryl groups are independently selected from
phenyl and substituted phenyl, wherein said substituted phenyl may be substituted
with one to three groups selected from C1 to C4 alkyl, halogen, hydroxy, cyano, carboxamido, nitro, and C1 to C4 alkoxy, and pharmaceutically acceptable salts thereof.
[0007] The compounds of the invention include all optical isomers of formula I (e.g. R and
S enantiomers) and their racemic and diastereomeric mixtures. When R
1 is
the R enantiomers at the chiral carbon designated by an asterisk in formula I are
preferred.
[0008] Unless otherwise indicated, the alkyl and alkenyl groups referred to herein, as well
as the alkyl moieties of other groups referred to herein (e.g. alkoxy), may be linear
or branched, and they may also be cyclic (e.g. cyclopropyl, cyclobutyl, cyclopentyl,
or cyclohexyl) or be linear or branched and contain cyclic moieties. Unless otherwise
indicated, halogen includes fluorine, chlorine, bromine, and iodine.
[0009] Preferred compounds of the formula I include those
wherein R1 is formula II; R2 is -R4, -OR4, R4-(CH2)b-NH(C=X)-(CH2)c-, or -(CH2)b-NH(C=O)-(CH2)c-R4; R3 is hydrogen or C1 to C6 alkyl; R4 is formula XV or formula XVII; A, B, D, E, and F are each independently C or N; R6, R7, R8, R9, R10, R15, R16, R17, R18, and R19 are each independently hydrogen, halogen, -CN, or -CR20; and R20 is C1 to C6 alkyl;
wherein R1 is formula III; R2 is -R4, -OR4, R4-(CH2)b-NH(C=X)-(CH2)c-, or -(CH2)b-NH(C=O)-(CH2)c-R4; R4 is formula XV or formula XVII; R3 is hydrogen or C1 to C6 alkyl; A, B, D, E, and F are each independently C or N; R6, R7, R8, R9, R10, R15, R16, R17, R18, and R18 are each independently hydrogen, halogen, -CN, or -OR20; and R20 is C1 to C6 alkyl;
wherein R1 is
R2 is -R4, -OR4, R4-(CH2)b-NH(C=X)-(CH2)c-, or -(CH2)b-NH(C=O)-(CH2)c-R4; R3 is hydrogen or C1 to C6 alkyl; R4 is formula XV or formula XVII; A, B, D, E, and F are each independently C or N; R6, R7, R8, R9, R10, R15, R16, R17, R18, and R19 are each independently hydrogen, halogen, -CN, or -OR20; and R20 is C1 to C6 alkyl;
wherein R1 is formula II, formula III, or formula IV; R2 is -R4; R3 is hydrogen or C1 to C6 alkyl; R4 is formula XVI; G, I, J, and K are each independently C, N, or O; L is C; R11, R12, R13, and R14 are each independently hydrogen, C1 to C6 alkyl, or C1 to C6 alkylaryl.
[0010] The following compounds are preferred:
7-Benzamido-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(1-Naphthylcarboxamido)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-Benzamido-1-(1-piperazinyl)-naphthalene;
7-Acetamido-1-(4-methyl-1-piperazinyl)-naphthalene;
7-Hexanamido-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(Phenylaminocarbonylamino)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(Benzyloxycarbonylamino)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(3-Nitro-2-pyridinylamino)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(5-Nitro-2-pyridylamino)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(3-Hydroxy-3-methyl-1-butynyl)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(2-Ethylsulfonyl)ethenyl-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(4-Chlorobenzyloxy)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(3-Methylaminosulfonylphenyl)-1-(4-methyl-1-piperazinyl)naphthalene;
7-(3-Methylsulfonylaminophenyl)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-Benzoyl-1-(4-methyl-1-piperazinyl)naphthalene;
7-(3-Methoxycarbonylphenyl)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(3-Fluorophenyl)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(Benzyloxy)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(4-Chlorobenzoyloxy)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(Imidazolo[4,5-b]pyridin-1-yl)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(Benzimidazol-1 -yl)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(5-Cyanobenzimidazol-1-yl)-1-(4-methyl-1 -piperazinyl)-naphthalene;
7-(1,2,3-Triazolo[4,5-b]pyridin-1-yl)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(5-Trifluoromethylbenzimidazol-1-yl)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(6,7-Dichlorobenzimidazol-1-yl)-1-(4-methyl-1-piperazinyl)-naphthalene;
2-[8-(4-Methylpiperazin-1-yl)naphthalen-2-yloxymethyl]quinoline;
1-Methyl-4-{7-[2-(4-chlorophenyl)thiazol-5-ylmethoxy]naphthalen-1-yl}piperazine;
1-Methyl-4-[7-(5-chloro-thiophen-2-ylmethoxy)napthalen-1-yl]piperazine;
8-(4-Methylpiperazin-1-yl)naphthalene-2-carboxylic acid phenylamide;
7-Amino-1-(1-methyl-4-piperidinyl)-naphthalene;
7-(3-Nitro-2-pyridylamino)-1-(1-methyl-4-piperidinyl)-naphthalene;
7-(Imidazolo[4,5-b]pyridin-1-yl)-1-(1-methyl-4-piperidinyl)-naphthalene;
7-(4-Chlorobenzamido-1-(1-methyl-4-piperidinyl)-naphthalene;
7-Amino-1 -(1-methyl-3-piperidinyl)-naphthalene;
7-(3-Nitro-2-pyridylamino)-1-(1-methyl-3-piperidinyl)-naphthalene;
7-(Imidazolo[4,5-b]pyridin-1-yl)-1-(1-methyl-3-piperidinyl)-naphthalene;
7-Benzamido-1-(1-methyl-3-piperidinyl)-naphthalene;
7-(4-Chlorobenzamido)-1-(4-methoxyethyl-1-piperazinyl)-naphthalene;
7-(4-Chlorobenzamido)-1-(4-propyl-1 -piperazinyl)-naphthalene;
7-(4-Chlorobenzamido)-1 -(4-ethyl-1-piperazinyl)-naphthalene;
7-Amino-1 -(1-methyl-3-pyrrolidinyl)-naphthalene;
7-Benzamido-1-(-methyl-3-pyrrolidinyl)-naphthalene;
7-Formamido-1-(pyrrolidin-2-(R)-ylmethyl)-naphthalene hydrochloride;
7-Amino-1-(1-piperazinyl)-naphthalene;
7-(Imidazolo-[4,5-b]-pyridin-1-yl)-1-(1-piperazinyl)-naphthalene; and
7-(1,2,3-Triazolo-[4,5-b]-pyridin-1-yl)-1-(1-piperazinyl)-naphthalene;
[0011] The following compounds are particularly preferred:
7-(Imidazolo[4,5-b]pyridin-1-yl)-1-(I-methylpyrrolidin-3-yl)naphthalene;
7-(4-Chlorobenzamido)-1-(pyrrolidin-2-(R)-ylmethyl)naphthalene;
2-[8-(4-Methylpiperazin-1-yl)naphthalen-2-yloxy]nicotinonitrile;
1 -(4-Methylpiperazin-1-yl)-7-pyrimidin-5-yl)naphthalene;
7-(5-Cyanopyridin-3-yl)-1-(4-methylpiperazin-1-yl)naphthalene;
1-(Piperazin-1-yl)-7-(pyrimidin-5-yl)naphthalene;
7-(4-Chlorobenzamido-1-(4-methylpiperazin-1 -yl)naphthalene;
7-(3-Methoxyphenyl)1-(4-methylpiperazin-1-yl)naphthalene;
7-(lmidazolo[4,5-b]pyridin-1-yl)-1-(4-methylpiperazin-1-yl)naphthalene;
8-(4-Methylpiperazin-1-yl)naphthalene-2-carboxylic acid 4-chlorobenzylamide;
7-Pyrimidin-2-yloxy-1-(4-methylpiperazin-1-yl)naphthalene;
7-(4-Methoxyphenyl)-1-(4-methylpiperazin-1-yl)-naphthalene;
7-(Benzimidazol-1-yl)-1-(4-methylpiperazin-1-yl)naphthalene; and
8-(1-Methylpiperidin-4-yl)naphthalene-2-carboxylic acid 4-chlorobenzylamide.
[0012] Other compounds believed to be most preferred are the following:
1-{7-[3-(4-Chloro-benzyl)-[1,2,4]oxadiazol-5-yl]-naphthalen-1-yl}-4-methylpiperazine;
4-{7-[3-(4-Chloro-benzyl)-[1,2,4]oxadiazol-5-yl]-naphthalen-1-yl}-1-methylpiperidine;
7-(3-Methoxyphenyl)-1-(1-methylpiperidin-4-yl)-naphthalene; and
7-(4-Methoxyphenyl)-1-(1-methylpiperidin-4-yl)-naphthalene.
[0013] The present invention also relates to a pharmaceutical composition for treating a
condition selected from hypertension, depression, anxiety, eating disorders, obesity,
drug abuse, cluster headache, migraine, pain, Alzheimer's disease, and chronic paroxysmal
hemicrania and headache associated with vascular disorders comprising an amount of
a compound of the formula I or a pharmaceutically acceptable salt thereof effective
in treating such condition and a pharmaceutically acceptable carrier.
[0014] The present invention also relates to a pharmaceutical composition for treating disorders
arising from deficient serotonergic neurotransmission (e.g., depression, anxiety,
eating disorders, obesity, drug abuse, cluster headache, migraine, pain and chronic
paroxysmal hemicrania and headache associated with vascular disorders) comprising
an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof
effective in treating such condition and a pharmaceutically acceptable carrier.
[0015] The present invention also relates to the use of a compound of formula I or a pharmaceutically
acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent
or carrier, for the manufacture of a medicament for the treatment of disorders arising
from deficient serotonergic neurotransmission.
[0016] The present invention also relates to the use of a compound of formula I or a pharmaceutically
acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent
or carrier, for the manufacture of a medicament for the treatment of a condition selected
from hypertension, depression, anxiety, eating disorders, obesity, drug abuse, cluster
headache, migraine, Alzheimer's disease, pain and chronic paroxysmal hemicrania and
headache associated with vascular disorders.
[0017] The present invention also relates to a compound of the formula
where R
1 is of the formulae
or
R
2 is (Methyl)
3Sn- or (Butyl)
3Sn-; R
3 is hydrogen , C
1 to C
6 alkyl, C
1 to C
6 alkylaryl, or aryl; a is 0, 1, or 2; and a broken line indicates the presence optionally
of a bond and the above aryl groups and the aryl moieties of the above alkylaryl groups
are independently selected from phenyl and substituted phenyl, wherein said substituted
phenyl may be substituted with one to three groups selected from C
1 to C
4 alkyl, halogen, hydroxy, cyano, carboxamido, nitro, and C
1 to C
4 alkoxy. These compounds include all optical isomers of formula I (e.g. R and S enantiomers)
and their racemic and diastereomeric mixtures. When R
1 is
the R enantiomers at the chiral carbon designated by an asterisk in formula I are
preferred. These compounds are useful as intermediates in preparing compounds of formula
I.
Detailed Description of the Invention
[0018] Compounds of formula I of this invention where R
1 is of the formula II are prepared by the following reaction of an α-tetralone of
formula V with a suitable piperazine of formula VI.
The so called enamines of formula VII are generally prepared by this reaction in
the presence of an acid catalyst such as, for example, p-toluenesulfonic acid or titanium
tetrachloride. If desired, the water formed as a by-product of the reaction may be
effectively removed from the reaction as it is formed by the use of a reagent such
as molecular sieves or calcium sulfate, or by azeotropic removal employing a Dean
Stark trap with a refluxing solvent. The reaction is typically run in a reaction inert
solvent such as benzene, toluene, tetrahydrofuran, or methylene chloride, at a temperature
of from about -78°C to about 150°C. When titanium tetrachloride is used as the acid
catalyst, the preferred temperature for the reaction is from about -78°C to about
25°C. When azeotropic water separation is employed, the preferred reaction temperature
is the boiling temperature of the particular reaction solvent.
[0019] In general, the α tetralones of formula V, for example, where R
2 is -OH, -NO
2, or -NH
2 are known in the literature and can be readily prepared by those skilled in the art,
such as, for example 7-amino-α-tetralone, (J. Med. Chem.,
1976, 19, 472) and 7-hydroxy-α-tetralone, (Tetrahedron Lett.,
1981, 22, 603). Other
α tetralones of formula V are readily prepared using the alkylation, acylation, and
organometallic reactions described herein and in standard synthesis texts, for example
Organic Synthesis,
Wiley, New York). The piperazines of formula VI are commercially available or can be made using methods
known in the art.
[0020] The enamines of formula VII may be converted to compounds of formula I by an oxidative
process. The reaction may be carried out using a variety of methods known in the art.
Among the acceptable oxidizing agents are noble metal catalysts, such as, palladium
or platinum on activated carbon if desired, chloranil, and sulfur. The reactions can
be carried out in a reaction inert solvent for example, toluene, xylene, tetrahydrofuran,
methylene chloride, preferably toluene or xylene, however a solvent is not always
necessary, especially for oxidations carried out with elemental sulfur. The oxidation
reactions generally proceed at a temperature of about 0°C to about 250°C. Preferred
temperatures for the oxidation depend on the particular oxidant in use and are about
60°C to about 150°C for noble metal catalytic oxidation, about 150°C to about 250°C
for sulfur oxidation and about 0°C to about 100°C for chloranil oxidations. From 1
to 5 equivalents, preferably 2-4 equivalents, of an additive such as dicyclopentadiene
or [2,2,2] bicyclooctene may be added to the reaction to reduce the amounts of enamine
reduction side products which may form competitively with the desired naphthalene
product.
[0021] Additional compounds of formula I may also be formed using standard chemical transformations
on other compounds of formula I. For example, when R
2 is R
4(C=O)NH- or R
4(C=O)O-, these groups may be hydrolyzed in the presence of aqueous acid or base to
form -NH
2 and -OH groups, respectively. These standard hydrolysis reactions may be carried
out in water with any of a variety of acids or bases (for example HCI, HBr, NaOH,
or KOH, preferably acid for amidehydrolysis and base for ester hydrolysis) and a cosolvent
(methanol or tetrahydrofuran, for example) may be used if desired to promote dissolution
of I in the medium. The reaction may be carried out at a temperature of from about
0°C to about 150°C. The preferred reaction temperature is about 20°C to about 40°C
for basic hydrolysis and about the boiling temperature of the mixture for acidic hydrolysis.
[0022] Additional compounds of formula I may be prepared by a reaction using an alkylating
or acylating agent (alkyl halide, mesylate, triflate, etc., or arylalkyl halide, mesylate,
triflate, etc., or an alkyl or aryl anhydride, or an alkyl or aryl carboxylic acid
chloride, etc.) with compounds of formula I where R
2 = -NH
2 or -OH. Suitable alkylating agents could include compounds of the formulae R
4-(CH
2)
b-Y or R
5-(CH
2)
b-Y where b is 0 to 3 and Y is a suitable leaving group, such as, for example, Br,
I, or triflate. Suitable acylating agents could include acid chlorides (e.g. R
4-(CH
2)
b-(C=O)-Cl or R
5-(CH
2)
b-(C=O)-Cl) or acid anhydrides (e.g. (R
4-(CH
2)
b-(C=O))
2-O or (R
5-(CH
2)
b-(C=O))
2-O, where b is 0 to 3). The reaction may be carried out in a reaction inert solvent
such as tetrahydrofuran and dichloroethane for the alkylating and acylating reactions.
Preferred solvents depend on the solubility of the reagents and the selection thereof
would be known to one skilled in the art. These alkylation or acylation reactions
are carried out at temperatures of between about 0°C to about 200°C depending on the
nature of the reaction. Preferred temperatures are between about 0°C to about 75°C
for the acylation reactions and between about 25°C to about 100°C for the alkylation
reactions.
[0023] Additional compounds of formula I may be prepared by the well known reductive alkylation
reaction of the compounds of formula I where R
2 is -NH
2 with aldehydes and ketones in the presence of hydrogen gas and a platinum or palladium
catalyst or in the presence of a reducing agent such as sodium cyanoborohydride.
[0024] Other compounds of formula I can be synthesized using an activated aromatic or heterocylic
compound, which are either commercially available or can be produced using methods
known in the art. To form the additional compounds, these reactants are reacted with
compounds of formula I where R
2 is OH or NH
2. As shown below, the term activated aromatic or heterocyclic compound implies a ring
compound of formulae VIII or IX;
where Y is a suitable leaving group (for example halogen or trifluoromethanesulfonyloxy)
and the ring is rendered susceptible to nucleophilic attack by the presence of one
or more nitrogen atoms in the ring or by the presence of one or more electron withdrawing
groups (in other words one or more of R
6, R
7, R
8, R
9, R
10, R
11, R
12, R
13, or R
14 are halogen, -CF
3, nitro, cyano, alkoxycarbonyl, amidocarbonyl, etc.) attached to the ring. Values
for A, B, D, E, F, G, I, J, K, and R
6, R
7, R
8, R
9, R
10, R
11, R
12, R
13, and R
14 may be selected from those described previously. Solvents suitable for use with the
activated aromatic or heterocylic compounds include, for example, dimethylformamide,
N-methypyrrolidinone, or methylene chloride and a base (for example triethylamine,
4-dimethylaminopyridine, sodium or potassium carbonate, sodium hydride) may be used
to facilitate the process if desired. Preferred solvents depend on the solubility
of the reagents and the selection thereof would be known to one skilled in the art.
These alkylation or acylation reactions are carried out at temperatures of between
about 0°C to about 200°C depending on the nature of the reaction. Preferred temperatures
are between about 50°C to about 125°C for these reactions.
[0025] The alkylation and acylation procedures described above can also be useful in synthesizing
of intermediates of formula V.
[0026] Compounds of formula I where R
2 is one of the claimed alkyl, alkenyl, or alkynyl moieties can be prepared by reaction
of compounds of formula I where R
2 is CF
3SO
3 with an appropriate olefin or acetylene compound in the presence of a palladium catalyst.
The selection of appropriate olefin or acetylene depends on the alkyl, alkenyl, or
alkynyl moiety desired in the end product, as would be appreciated by one skilled
in the art. The alkenyl and alkynyl substituted compounds can be produced using the
following reaction scheme:
The catalyst may be selected from those typically employed for the so-called Heck
reaction (palladium acetate, palladium chloride, bis (acetonitrile) palladium chloride,
for example). The reaction is carried out neat or in a reaction inert solvent such
as acetonitrile, dimethylformamide, or N-methylpyrrolidinone. The reaction is conveniently
run at 20°C to 160°C, preferably 60°C to 130°C. The details of reactions of this type
have been well described in the literature (Organic Reactions
1982, 27, 345).
[0027] The synthesis of compounds having the claimed alkyl moieties require the additional
step of reducing the product of the reaction discussed in the previous paragraph.
The reduction is performed using standard methods known in the art.
[0028] The Heck reaction can also be useful in the synthesis of intermediates of formula
V, as is known in the art.
[0029] The compounds of formulae I and intermediates of formula V where R
2 is CF
3SO
3 can be prepared by reacting the corresponding R
2 substituted hydroxy compounds of formulae I or V with an activated form of triflic
acid, for example, triflic anhydride, acid chloride, N-phenyltrifluoromethanesulfonimide,
preferably triflic anhydride, typically in the presence of a base, such as, for example,
triethylamine or diisopropylethylamine, preferably triethylamine. The reaction may
be run in an inert solvent, such as, tetrahydrofuran or methylene chloride, at a temperature
of from about -78°C to about 25°C, preferably below about 0°C. This procedure is known
in the art, as shown, for example, in J. Amer. Chem. Soc.,
1987, 109, 5478.
[0030] A method to prepare the compounds of formula I where R
2 is R
4 or R
4(CH
2)
b(C=O)(CH
2)
c- is accomplished by reacting compounds of formula I where R
2 is trimethylstannyl or tributylstannyl with an aryl or vinyl halide, or an aryl or
vinyl triflate, or an aryl or alkyl acid chloride or a heteroaryl halide or triflate
in the presence of a catalyst, preferably tetrakis(triphenylphosphine)palladium or
tris(dibenzylideneacetone)dipalladium, and is shown in the following reaction scheme:
[0031] The procedures and conditions to carry out this reaction are known to those in the
art, for example, in Angew. Chem. Int. Ed. Engl.,
1986, 25, 508.. The triflate variant of this reaction is also known in the art, for example,
in J. Amer. Chem. Soc.,
1987, 109, 5478. A further variation of this type of process which uses an alkyl or aryl
halide in the presence of carbon monoxide gas and a palladium catalyst is also known,
for example, in J. Amer. Chem. Soc.,
1988, 110, 1557.
[0032] It will be recognized by one skilled in the art that the coupling reactions described
above may also be used to prepare the intermediates of formula V.
[0033] The stannane compounds I and V may be prepared from the compound I (R
2 being CF
3SO
3) following known literature procedures (J. Amer. Chem. Soc.,
1987, 109, 5478).
[0034] A method to prepare compounds of formula I where R
2 is R
4 is accomplished by reacting compounds of formula I where R
2 is bromo, iodo, or -OSO
2CF
3 with an arylstannane, arylboronic acid, heteroaryl boronic acid, or heteroarylstannane
in the presence of a catalyst, preferably tetrakis(triphenylphosphine)palladium, in
an inert solvent, and is shown in the following scheme:
The procedures and conditions to carry out this reaction are known to those skilled
in the art, for example, in Angew. Chem. Int. Ed. Engl.,
1986, 25, 508. The triflate variant of this reaction is also known in the art, for example,
in J. Am. Chem. Soc.,
1987, 109, 5478. The required arylstannanes or heteroarylstannanes are available by methods
known to one skilled in the art, for example, in J. Am. Chem. Soc,
1987, 109, 5478. The procedure and conditions for boronic acid couplings are described
in J. Org. Chem.
1993, 58, 2208.
[0035] A method of preparing compounds of formula I and intermediates of formula V where
R
2 is -O-R
4 is to react corresponding compounds of formula I or intermediates of formula V where
R
2 is -OH with alcohols, for example, ethanol or benzyl alcohol, in the presence of
triphenylphosphine and diethyl azodicarboxylate in a Mitsunobu reaction. Mitsunobu
reactions are known in the art, for example, as disclosed in Synthesis
1981, 1.
[0036] Further compounds of formula 1 where R
2 is R
4-(CH
2)
b-O-(C=O)-(CH
2)
c- or R
4(CH
2)
b-NH-(C=X)-(CH
2)
c- and c is 0 may be prepared by reaction of compounds of the formula I where R
2 is OSO
2CF
3 with an alcohol or an amine and carbon monoxide in the presence of a palladium catalyst.
Hydrolysis of the resulting esters or amides to the corresponding acids and treatment
following the general procedures outlined in EP 0 438 230 A2 further allow the preparation
of additional compounds of formula I where R
2 is -R
4 and R
4 is of formula XVI [e.g., a (1,2,4-oxadiazol-5-yl)-naphthalene].
[0037] Compounds of formula I may also be prepared using standard functional group manipulations
known in the art and which are disclosed in various standard synthetic chemistry texts.
Examples of these are discussed below.
[0038] When R
2 is R
4(CH
2)
b(C=O)(CH
2)
c-, it may be reacted with a reducing agent, to yield the corresponding alcohol. Standard
methods known in the art can be used. Useful reducing agents include sodium borohydride,
lithium aluminum hydride, or borane (or any of its complexes).
[0039] Compounds of formula I where the R
2 substituent includes a ketone or ester carbonyl moiety may be treated with organometallic
agents, such as alkyl- and aryl lithiums, or Grignard reagents using methods known
in the art. In this reaction, the resulting compounds will be tertiary alcohols (R
2 = -C(OH)R
4R
5).
[0040] When R
2 contains an amide group, treatment with a reducing agent, such as, for example, lithium
aluminum hydride or borane using known methods, produces the corresponding alkylated
(or aralkylated) secondary or tertiary amines.
[0041] Another example of the interconversion of compounds of formula I is the reduction
of a nitro group of an R
2 substituent including a nitrophenyl or nitropyridyl group to the corresponding amine.
For example, as shown below,
where R
1 and Z are as defined above, the reaction may be carried out using known nitro group
reducing agents and methods, for example, hydrogenation over noble metal catalysts
(palladium or platinum on a support, such as carbon, if desired) or by dissolving
metal reduction.
[0042] In a further example of the interconversion of the compounds of formula I, the product
of the previous reaction scheme may be cyclized with, for example, dimethylformamide
dimethyl acetal or triethyl orthoformate to produce fused imidazole compounds of formula
I, as shown below,
[0043] The reaction may be carried out in an inert solvent, such as, for example, dimethylformamide,
ethanol, or dimethyl sulfoxide, preferably dimethylformamide. The reaction is run
at a temperature of from about 20 °C to about 125°C. If desired, an acid catalyst,
such as, p-toluenesulfonic acid or camphor sulfonic acid, preferably p-toluenesulfonic
acid, may also be used to facilitate the reaction. In some cases the amidine compounds
of formula I can be isolated, especially when the acid catalyst is not used.
[0044] Another method to carry out the reaction shown in the previous scheme employs diethyl
ethoxymethylenemalonate, ethoxymethylenemalononitrile, or related reagents preferably
ethoxymethylenemalononitrile, as the cyclization reagent. This reaction may be run
in an inert solvent, such as, acetic acid, ethanol, or isopropanol, preferably isopropanol
or acetic acid. The reaction temperature should be from about 25°C to about 150°C.
The preferred temperature is the reflux temperature of the solvent for convenience
and to decrease the reaction time.
[0045] Compounds of formula I where R
1 is tetrahydropyridine, piperidine, or azacycloalkylmethyl may be prepared from 8-bromo-β-tetralone,
which is known in the art, for example in U.S. Patent No. 4,897,405, as shown in the
following reaction scheme:
[0046] The 8-bromo-β-tetralone is first reacted with an amine, for example, dibenzylamine
to form an enamine X using the same procedure disclosed previously on page 8. The
enamine X can be dehydrogenated as described above on page 9, chloranil being the
preferred reagent with these particular reactants, to yield 1-bromo-7-amine substituted
naphthalenes XI. Selection of an appropriate amine for the enamine-forming step would
be apparent to one skilled in the art, for example, diallylamine and dibenzylamines
for instance. Compounds XI can be then treated with vinylstannanes, for example, 1-BOC-4-trimethylstannyl-1,2,5,6-tetrahydropyridine
(BOC=tert-butyloxycarbonyl), shown in the above scheme, in the presence of a catalyst.
Palladium is the preferred catalyst, for example (Ph
3P)
4Pd or Pd
2(dba)
3 and the reaction follows the same procedures as described above on pages 12 to 14,
where R
1 is tetrahydropyridine in a so-called Stille and Heck reactions.
[0047] Compounds of formula I where R
1 is piperidine can be prepared by catalytic hydrogenation of the tetrahydropyridine
from the previous paragraph, using standard methods known in the art, generally with
palladium on carbon as the catalyst. Compounds I where R
1 is piperidine or tetrahydropyridine can be produced, for example, by removal of the
benzyl groups (when R
2 is dibenzylamino) by catalytic hydrogenolysis, using a suitable catalyst such as
palladium hydroxide, palladium on carbon, or platinum on carbon, preferably palladium
hydroxide. The reaction is performed in an inert solvent, such as ethanol or ethyl
acetate, either with or without a profic acid, such as acetic acid or HCI. The preferred
acid is acetic acid. In this case, the resulting compounds are of formula I where
R
2 is amino. The amino group can be derivatized using standard techniques known in the
art and as described previously on pages 10 to 16 to afford further compounds of formula
I with substituted amines.
[0048] Compounds of formula XI from the previous reaction scheme may also be treated with
alkyllithium reagents, for example, butyllithium, sec-butyllithium or tert-butyllithium,
preferably butyllithium in an inert solvent, as shown below,
[0049] Suitable solvents include, for example, ether or tetrahydrofuran, preferably tetrahydrofuran.
Reaction temperatures range from about -110°C to about 0°C. The intermediate lithium
anions of formula XII thus formed may then be further reacted with a suitable electrophile,
selection of which depends on the desired substituent at the R
1 position. Suitable electrophiles to prepare compounds I where R
1 is formula III or IV include, for example, carbonyl derivatives or alkylating agents
(e.g., 1-BOC-4-piperidone, 1-BOC-prolinal or 1-FMOC-2-chloromethylpyrrolidine (FMOC=fluorenylmethoxycarbonyl)).
[0050] In the case where an aldehyde or ketone is used as the electrophile, the intermediates
XIII, XIV, or XX which are formed require that the hydroxy group be removed so as
to result in compounds of formula I as shown below,
[0051] This step may be accomplished by one of several standard methods known in the art.
For example, a thiocarbonyl derivative (for example a xanthate) may be prepared and
removed by a free radical process, both of which are known to those skilled in the
art. Alternatively, the hydroxyl group may be removed by reduction with a hydride
source such as triethylsilane under acidic conditions, using such as, for example,
trifluoroacetic acid or boron trifluoride. The reduction reaction can be performed
neat or in a solvent, such as methylene chloride. A further alternative would be to
first convert the hydroxyl group to a suitable leaving group, such as tosylate or
chloride, using standard methods. The leaving group is then removed with a nucleophilic
hydride, such as, for example, lithium aluminum hydride. This last reaction is performed
typically in an inert solvent, such as, ether or tetrahydrofuran. Also, a reducing
agent may be used to reductively remove of the benzylic substituent. Suitable reducing
agents include, for example, Raney nickel in ethanol, or sodium or lithium in liquid
ammonia. Another alternative method for removing the hydroxyl group is to first dehydrate
the alcohol XIII, XIV, or XX to an olefin with a reagent such as Burgess salt
(J. Org. Chem., 1973,
38, 26) followed by catalytic hydrogenation of the double bond under standard conditions
with a catalyst such as palladium on carbon. The alcohol may also be dehydrated to
the olefin by treatment with acid such as p-toluenesulfonic acid. For XIII the free
radical procedure is preferred because it preserves the stereochemical integrity of
the chiral center. For XIV or XX the Burgess salt or acid dehydration procedures are
preferred.
[0052] In the case where R
2 is, for example, dibenzylamino, additional compounds of formula I may be prepared
by hydrogenolysis and derivatization as described above on pages 10 to 16.
[0053] 8-bromo-β-tetralone, discussed earlier, may also be utilized to form other compounds
of formula I, as shown below,
[0054] 8-bromo-β-tetralone is first dehydrogenated to form 1-bromo-7-hydroxynaphthalene
using an oxidizing reagent, such as, for example, elemental sulfur as described above
on page 8 or N-bromosuccinimide. An appropriate protecting group is then used to protect
the hydroxyl group if desired, formation and selection being within the knowledge
of one skilled in the art (e.g., Greene and Wuts, Protective Groups in Organic Synthesis,
2nd edition, Wiley, New York, 1991). This is followed by subsequent replacement of
the bromo substituent using methods described previously on pages 16 to 18. After
replacement of the bromo substituent, the hydroxyl protecting group may be removed
using standard chemistry, and the free hydroxyl group may be derivatized as described
above on pages 10 to 14 to afford compounds of formula I wherein R
2 is attached to the naphthalene ring via a carbon or oxygen atom. In some cases the
protecting group may also serve as an activating group for further transformations,
CF
3SO
3 for example, as described earlier on pages 12 to 14 or may simply be the final R
2 moiety.
[0055] Unless indicated otherwise, the pressure of each of the above reactions is not critical.
Generally, the reactions will be conducted at a pressure of about one to about three
atmospheres, preferably at ambient pressure (about one atmosphere).
[0056] The compounds of the formula I which are basic in nature are capable of forming a
wide variety of different salts with various inorganic and organic acids. Although
such salts must be pharmaceutically acceptable for administration to animals, it is
often desirable in practice to initially isolate a compound of the formula I from
the reaction mixture as a pharmaceutically unacceptable salt and then simply convert
the latter back to the free base compound by treatment with an alkaline reagent, and
subsequently convert the free base to a pharmaceutically acceptable acid addition
salt. The acid addition salts of the base compounds of this invention are readily
prepared by treating the base compound with a substantially equivalent amount of the
chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic
solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the
desired solid salt is obtained.
[0057] The acids which are used to prepare the pharmaceutically acceptable acid addition
salts of the base compounds of this invention are those which form non-toxic acid
addition salts, i.e., salts containing pharmacologically acceptable anions, such as
hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate
or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate,
succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and
pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
[0058] Those compounds of the formula I which are also acidic in nature, e.g., where R
2 contains a carboxylate, are capable of forming base salts with various pharmacologically
acceptable cations. Examples of such salts include the alkali metal or alkaline-earth
metal salts and particular, the sodium and potassium salts. These salts are all prepared
by conventional techniques. The chemical bases which are used as reagents to prepare
the pharmaceutically acceptable base salts of this invention are those which form
non-toxic base salts with the herein described acidic compounds of formula I. These
non-toxic base salts include those derived from such pharmacologically acceptable
cations as sodium, potassium, calcium and magnesium, etc. These salts can easily be
prepared by treating the corresponding acidic compounds with an aqueous solution containing
the desired pharmacologically acceptable cations, and then evaporating the resulting
solution to dryness, preferably under reduced pressure. Alternatively, they may also
be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired
alkali metal alkoxide together, and then evaporating the resulting solution to dryness
in the same manner as before. In either case, stoichiometric quantities of reagents
are preferably employed in order to ensure completeness of reaction of maximum product
of yields of the desired final product.
[0059] The compounds of the formula I and the pharmaceutically acceptable salts thereof
(hereinafter, also referred to as the active compounds of the invention) are useful
psychotherapeutics and are potent serotonin (5-HT
1) agonists and antagonists and may be used in the treatment of depression, anxiety,
eating disorders, obesity, drug abuse, cluster headache, migraine, chronic paroxysmal
hemicrania and headache associated with vascular disorders, pain, and other disorders
arising from deficient serotonergic neurotransmission such as Alzheimer's disease.
The compounds can also be used as centrally acting antihypertensives and vasodilators.
[0060] The affinities of the compounds of this invention for the various serotonin 1 receptors
are evaluated using standard radioligand binding assays as described in the literature.
The 5-HT
1A affinity is measured using the procedure of Hoyer et al. (Brain Res.,
1986, 376, 85). The 5-HT
1C affinity is measured using the procedure of Pazos et al. (Eur. J. Pharmacol.,
1985, 106, 539). The 5-HT
1D affinity is measured using the procedure of Heuring and Peroutka (J. Neurosci.,
1987, 7, 894).
[0061] The compositions of the present invention may be formulated in a conventional manner
using one or more pharmaceutically acceptable carriers. Thus, the active compounds
of the invention may be formulated for oral, buccal, intranasal, parenteral (e.g.,
intravenous, intramuscular or subcutaneous) or rectal administration or in a form
suitable for administration by inhalation or insufflation.
[0062] For oral administration, the pharmaceutical compositions may take the form of, for
example, tablets or capsules prepared by conventional means with pharmaceutically
acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone
or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose
or calcium phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants
(e.g. potato starch or sodium starch glycolate); or wetting agents (e.g. sodium lauryl
sulphate). The tablets may be coated by methods well known in the art. Liquid preparations
for oral administration may take the form of, for example, solutions, syrups or suspensions,
or they may be presented as a dry product for constitution with water or other suitable
vehicle before use. Such liquid preparations may be prepared by conventional means
with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol
syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g. lecithin
or acacia); non-aqueous vehicles (e.g. almond oil, oily esters or ethyl alcohol);
and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbid acid).
[0063] For buccal administration the composition may take the form of tablets or lozenges
formulated in conventional manner.
[0064] The active compounds of the invention may be formulated for parenteral administration
by injection, including using conventional catheterization techniques or infusion.
Formulations for injection may be presented in unit dosage form, e.g. in ampules or
in multi-dose containers, with an added preservative. The compositions may take such
forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may
contain formulating agents such as suspending, stabilizing and/or dispersing agents.
Alternatively, the active ingredient may be in powder form for reconstitution with
a suitable vehicle, e.g. sterile pyrogen-free water, before use.
[0065] The active compounds of the invention may also be formulated in rectal compositions
such as suppositories or retention enemas, e.g., containing conventional suppository
bases such as cocoa butter or other glycerides.
[0066] For intranasal administration or administration by inhalation, the active compounds
of the invention are conveniently delivered in the form of a solution or suspension
from a pump spray container that is squeezed or pumped by the patient or as an aerosol
spray presentation from a pressurized container or a nebulizer, with the use of a
suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane,
carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage
unit may be determined by providing a valve to deliver a metered amount. The pressurized
container or nebulizer may contain a solution or suspension of the active compound.
Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or
insufflator may be formulated containing a powder mix of a compound of the invention
and a suitable powder base such as lactose or starch.
[0067] A proposed dose of the active compounds of the invention for oral, parenteral or
buccal administration to the average adult human for the treatment of the conditions
referred to above (e.g., migraine) is 0.1 to 200 mg of the active ingredient per unit
dose which could be administered, for example, 1 to 4 times per day.
[0068] Aerosol formulations for treatment of the conditions referred to above (e.g., migraine)
in the average adult human are preferably arranged so that each metered dose or "puff"
of aerosol contains 20
µg to 1000
µg of the compound of the invention. The overall daily dose with an aerosol will be
within the range 100
µg to 10 mg. Administration may be several times daily, for example 2, 3, 4 or 8 times,
giving for example, 1, 2 or 3 doses each time.
[0069] The following Examples illustrate the preparation of the compounds of the present
invention. Melting points are uncorrected. NMR data are reported in parts per million
(δ) and are referenced to the deuterium lock signal from the sample solvent (deuteriochloroform
unless otherwise specified). Specific rotations were measured at room temperature
using the sodium D line (589 nm). Commercial reagents were utilized without further
purification. THF refers to tetrahydrofuran. DMF refers to dimethylformamide. Chromatography
refers to column chromatography performed using 32-63
µm silica gel and executed under nitrogen pressure (flash chromatography) conditions.
Room or ambient temperature refers to 20-25°C. All non-aqueous reactions were run
under a nitrogen atmosphere for convenience and to maximize yields. Concentration
at reduced pressure implies the use of a rotary evaporator.
[0070] The terms 1-piperazinyl and piperazin-1-yl, 1-piperidinyl and piperidin-1-yl, and
3-pyrrotidinyl and pyrrolidin-3-yl are used interchangeably throughout this document.
Triflate refers to -OSO
2CF
3 or CF
3SO
3.
Example 1
7-Benzamido-1-(4-methyl-1-piperazinyl)-naphthalene
[0071] 7-Amino-α-tetralone (42.15 g, 0.262 mol) was dissolved in dry THF (1000 mL) and triethylamine
(38.3 mL, 0.288 mol) was added. The mixture was chilled to 0°C and benzoyl chloride
(33.4 mL, 0.288 mol) was added dropwise with a THF (10 mL) rinse. The mixture was
mechanically stirred overnight, then the solvent was removed with a nitrogen stream.
The residues were taken up in methylene chloride and extracted with 1N HCI, water,
saturated sodium bicarbonate, and brine. The organic phase was further dried over
calcium sulfate and concentrated to a solid mass. Recrystallization from ethanol (650
mL) yielded 52 g of 7-benzamido-
a-tetralone. Concentration of the mother liquors yielded another 6 g for a total yield
of 58.9 g (85%): mp 153-156°C. Analysis calculated for C
17H
14NO
2: C, 77.25; H, 5.34; N, 5.30. Found: C, 77.05; H, 5.57; N, 5.30.
[0072] 7-Benzamido-
α-tetralone (5.0 g, 18.95 mmol) was dissolved in dry THF (107 mL) and N-methyl-piperazine
(6.3 mL, 56.8 mmol) was added. The solution was cooled to -78°C and titanium tetrachloride
(2.5 mL, 22.75 mmol) in methylene chloride (30 mL) was added dropwise. The mixture
was stirred overnight and during this time a fine green precipitate formed. The solvent
was removed under a stream of nitrogen and the residue was stirred vigorously in a
mixture of ethyl acetate and 5N ammonium hydroxide for 2 hours. The solid which formed
was collected, washed with ethyl acetate and then ether, and dried in vacuo. The filtrate
was discarded. The solid was vigorously stirred with 1N sodium hydroxide (100 mL)
and methylene chloride (100 mL) for 2 hours. The solid which did not dissolve was
removed by filtration. The phases were separated from the filtrate and the organic
layer was washed with brine, dried over calcium sulfate and concentrated to give 1.01
g of product. The solid was now stirred with dimethyl sulfoxide (DMSO, 150 mL) for
2 hours and filtered again. The undissolved material was discarded. The DMSO was removed
at reduced pressure and the residue was taken up in methylene chloride. This organic
solution was treated with brine which removed the last traces of DMSO from the organic
phase and caused immediate precipitation of 2.29 g more product which was collected
and dried. The phases were separated from the filtrate. The organic layer was dried
over sodium sulfate and concentrated to leave 2.13 g of light tan solid product. In
this fashion 5.43 g, 83% of 7-benzamido-1-(4-methyl-1-piperazinyl)-3,4-dihydronaphthalene
was obtained;
1HNMR (CDCl
3)
δ 7.88 (dd,
J = 1.5, 8 Hz, 2H), 7.77 (br s, 1H), 7.59 (d,
J = 2 Hz, 1 H), 7.56-7.46 (m, 4H), 7.16 (d,
J = 8 Hz, 1H), 5.32 (t,
J = 4.5 Hz, 1H), 2.88 (br s, 4H), 2.69-2.55 (m, 6H), 2.36 (s, 3H), 2.27-2.17 (m, 2H).
[0073] A mixture of xylene (500 mL) and 10 % Palladium on carbon (2.0 g) was refluxed overnight
with azeotropic removal of water by means of a Dean-Stark trap containing 4 Å molecular
sieves. The mixture was cooled to room temperature and 7-benzamido-1-(4-methyl-1-piperazinyl)-3,4-dihydronaphthalene
(5.44 g, 15.67 mmol) was added. The mixture was heated at reflux for 2 hours, cooled,
and filtered through a Celite pad. The filtrate was concentrated in vacuo and purified
by silica gel flash chromatography (1.5 x 4 inches). Elution with 50 to 85% ethyl
acetate/hexane gave 7-benzamido-α-tetralone (0.636 g). Continued elution with 95%
ethyl acetate / hexane and pure ethyl acetate gave 1.37 g of title product followed
by 1.95 g of a 2:1 mixture of title product and 7-benzamido-1-(4-methylpiperazinyl)-1,2,3,4-tetrahydronaphthalene.
The 1.95 g mixture was rechromatographed as above to yield 1.0 g more pure title product.
In this manner 2.37 g, 43% was obtained: mp 173-175°C. Analysis calculated for C
22H
23N
3O: C, 76.49; H, 6.71; N, 12.16. Found: C, 75.94; H, 6.39; N, 11.95.
Example 2
7-Amino-1-(4-methyl-1-piperazinyl)-naphthalene
[0074] 7-Benzamido-1-(4-methyl-1-piperazinyl)-naphthalene (the product from example 1, 3.75
g, 10.87 mmol) was slurried in 6N HCI (a mixture of concentrated HCI (25 mL) and ethanol
(25 mL)) (50 mL) and refluxed for 3.5 hours. The mixture was cooled and brought to
pH 10 with 1 N sodium hydroxide. The aqueous mixture was extracted with methylene
chloride. The organic layer was washed with brine, dried over calcium sulfate and
concentrated to afford 2.44 g (92 %) of the title product which was suitable for use
in further reactions without purification. A sample was recrystallized from isopropyl
alcohol for analysis: mp 157-159°C;
1H NMR δ 7.65 (d,
J = 8.5 Hz, 1H), 7.44 (d,
J = 8 Hz, 1H), 7.35 (d,
J = 2 Hz, 1H), 7.17 (t,
J = 8 Hz, 1H), 7.04 (d with long range coupling,
J = 7 Hz, 1H), 6.94 (dd,
J = 2.5, 8.5 Hz, 1H), 3.88 (br s, 3H), 3.12 (br s, 4H), 2.42 (s, 3H). Analysis calculated
for C
15H
19N
3: C, 74.65; H, 7.94; N, 17.41. Found: C, 74.79; H, 8.14; N, 17.41.
Example 3
7-(2-Naphthylcarboxamido)-1-(4-methyl-1-piperazinyl)-naphthalene
[0075] A solution of 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.197 g, 0.817 mmol)
and triethylamine (0.217 mL, 1.63 mmol) in acetonitrile (10 mL) was chilled to 0°C
and 2-naphthoyl chloride (0.311 g, 1.63 mmol) was added. The solution was refluxed
overnight. The solvent was removed at reduced pressure and the residue was taken up
in methylene chloride. The mixture was stirred vigorously with saturated sodium bicarbonate
for 2 hours and the phases were separated. The organic layer was dried over calcium
sulfate and concentrated to a tan foam which was purified by flash chromatography
on silica gel (1 x 3 inches). Ethyl acetate/hexane gradient elution of from 25:75
to 75:25 followed by ethyl acetate and finally 5% ethanol/ethyl acetate gave 0.31
g of light yellow foam. Trituration with hexane yielded 0.235 g (72%) of the title
product as an amorphous solid: mp 95-130°C. High resolution mass Spectrum (HRMS) m/e
calculated for C
26H
25N
3O: 395.1994. Observed m/e: 395.1981.
Example 4
7-(3-Nitrobenzamido)-1-(4-methyl-1-piperazinyl)-naphthalene
[0076] The title product was prepared following the procedure of example 3 from 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene
(0.15 g, 0.622 mmol) and triethylamine (0.09 mL, 0.68 mmol) and 3-nitrobenzoyl chloride
(0.127 mL, 0.684 mmol) in acetonitrile (10 mL) with an overnight reflux. The product
was purified by silica gel flash chromatography followed by recrystallization from
ethyl acetate to yield 0.116 g (47%) of the title product: mp 182-184°C. Analysis
calculated for C
22H
22N
4O
3: C, 67.68; H, 5.68; N, 14.35. Found: C, 67.47; H, 5.64; N, 14.08.
Example 5
7-(1-Naphthylcarboxamido)-1-(4-methyl-1-piperazinyl)-naphthalene
[0077] The title product was prepared following the procedure of example 3 from 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene
(0.227 g, 0.94 mmol) and triethylamine (0.133 mL, 0.1.32 mmol) and 1 -naphthalenecarboxylic
acid chloride (0.25 g, 1.32 mmol) in acetonitrile (10 mL) with stirring overnight
at room temperature. The product was purified and after chromatography and recrystallization
from ethyl acetate yielded 0.213 g (57%) of the title compound and had; mp 217-218°C.
Analysis calculated for C
26H
25N
3O: C, 78.96, H, 6.37; N, 10.62. Found: C, 78.66; H, 6.33; N, 10.48.
Example 6
7-(3-Chlorobenzamido)-1-(4-methyl-1-piperazinyl)-naphthalene
[0078] The title product was prepared following the procedure of example 3 from 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene
(0.24 g, 0.995 mmol) and triethylamine (0.146 mL, 1.09 mmol) and 3-chlorobenzoyl chloride
(0.138 mL, 1.09 mmol) in acetonitrile (10 mL) with overnight stirring at room temperature.
The product was isolated using flash chromatography and trituration from hexane and
recrystallization from ethyl acetate (with a seed crystal) to yield 0.076g (20%) of
the title compound: mp 147-148°C. HRMS m/e calculated for C
22H
22ClN
3O: 379.1448. Observed m/e: 379.14473. Analysis calculated for C
22H
22ClN
3O: C, 69.56; H, 5.84; N, 11.06. Found: C, 68.95; H, 5.81; N, 10.96.
Example 7
7-(3,5-Dinitrobenzamido)-1-(4-methyl-1-piperazinyl)-naphthalene
[0079] The title product was prepared following the procedure of example 3 from 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene
(0.15 g, 0.622 mmol) and triethylamine (0.09 mL, 0.68 mmol) and 3,5-dinitrobenzoyl
chloride (0.158 g, 0.684 mmol) in acetonitrile (10 mL) with overnight stirring at
room temperature. The product was purified using chromatography and recrystallization
from acetonitrile to yield 0.17 g (63%) of the title compound: mp 254-256°C. Analysis
calculated for C
22H
21N
5O
5: C, 60.68; H, 4.86; N, 16.08. Found: C, 60.59; H, 4.73; N, 15.88.
Example 8
7-(4-Chlorobenzamido)-1-(4-methyl-1-piperazinyl)-naphthalene
[0080] The title product was prepared following the procedure of example 3 from 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene
(0.249 g, 1.03 mmol) and triethylamine (0.151 mL, 1.14 mmol) and 4-chlorobenzoyl chloride
(0.241 g, 1.14 mmol) in acetonitrile (10 mL) with overnight stirring at room temperature.
The product was purified using chromatography and recrystallization from ethyl acetate
to yield 0.17 g (43%) of the title compound as a white solid mp 174-175°C. HRMS m/e
calculated for C
22H
22ClN
3O: 379.1448. Observed m/e: 379.1465. Analysis calculated for C
22H
22ClN
3O: C, 69.56; H, 5.84; N, 11.06. Found: C, 69.38; H, 5.80; N, 10.96.
Example 9
7-(3-Cyanobenzamido)-1-(4-methyl-1-piperazinyl)-naphthalene
[0081] The title product was prepared following the procedure of example 3 from 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene
(0.213 g, 0.883 mmol) and triethylamine (0.258 mL, 1.94 mmol) and 3-cyanobenzoyl chloride
(0.322 g, 1.94 mmol) in acetonitrile (10 mL) with stirring at reflux for 2 hours and
then at room temperature overnight. The mixture was concentrated and the residue was
taken up in methylene chloride. This organic solution was washed with 0.5
N sodium hydroxide, dried over calcium sulfate and concentrated. The product was isolated
by silica gel flash chromatography and recrystallization from isopropyl alcohol to
yield 0.184 g of (60%) of the title compound: mp 220-222°C. Analysis calculated for
C
23H
22N
4O: C, 74.57; H, 5.99; N, 15.12. Found: C, 74.42; H, 5.78; N, 14.96.
Example 10
7-(4-Hydroxybenzamido)-1-(4-methyl-1-piperazinyl)-naphthalene
[0082] A mixture of 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.118 g, 0.489 mmol)
and triethylamine (0.13 mL, 0.98 mmol) in acetonitrile (10 mL) was chilled to 0°C
and 4-triisopropylsilyloxybenzoyl chloride (0.16 g, 0.51 mmol) dissolved in methylene
chloride was added all at once. The mixture was gently refluxed overnight; then 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene
(0.038 g, 0.16 mmol), 4-triisopropylsilyloxybenzoyl chloride (0.5 g, 1.6 mmol), and
triethylamine (0.13 mL, 0.93 mmol) were added. The reaction was refluxed for an additional
24 hours, cooled and the solvent was removed at reduced pressure. The residue was
partitioned between methylene chloride and saturated aqueous sodium bicarbonate and
stirred vigorously for 5 hours. The phases were separated and the organic layer was
washed with brine, dried over calcium sulfate and concentrated to a tan foam which
was purified by flash chromatography on silica gel (1 x 3.5 inches). Elution with
25% ethyl acetate/hexane removed unweighed recovered acid chloride. Continued elution
with an ethyl acetate/hexane gradient of from 1:3 to 3:1 followed by 100% ethyl acetate
gave 0.238 g of 7-(4-triisopropylsilyloxybenzamido)-1-(4-methyl-1-piperazinyl)-naphthalene
as a viscous tan oil.
[0083] The product of the above reaction was dissolved in dry THF (10 mL) and tetrabutylammonium
fluoride (0.47 mL, 0.47 mmol, 1M in THF solution) was added dropwise. The solution
darkened and was stirred 2 hours followed by addition of 0.2 mL more tetrabutylammonium
fluoride. After stirring an additional 3 hours, the solvent was removed and the residue
was taken up in ethyl acetate. This organic phase was washed with water and brine,
dried over calcium sulfate and concentrated to a white foam. This foam was flash chromatographed
on silica gel (1 x 4 inches). Gradient elution with ethyl acetate/hexane of from 1:3
to 3:1 gave nil. Continued elution with 5% ethanol/ethyl acetate gave first the title
product (0.04 g) which was about 80 % pure followed by an additional 0.02 g of pure
product. The 0.02 g sample was triturated with ether / hexane and yielded 0.006 g
(1.9%) of title product as a tan solid: mp 156-160°C. HRMS m/e calculated for C
22H
23N
3O
2: 361.1789. Observed m/e: 361.1787.
Example 11
7-Benzamido-1-(1-piperazinyl)-naphthalene
[0084] The title product from Example 1 (0.50 g, 1.45 mmol) was dissolved in methylene chloride
(10 mL) and chilled to 0°C. 1-chloroethyl chloroformate (0.156 mL, 1.45 mmol) was
added via syringe. The mixture was allowed to come to room temperature and then refluxed
3 hours. Additional 1-chloroethyl chloroformate (0.1 mL, 0.93 mmol) was added and
the mixture was further refluxed overnight. Methanol (10mL) was added and the reaction
was refluxed for 2 hours. The mixture was concentrated and the residue was taken up
in methylene chloride and extracted with 1 N NaOH and brine. The organic phase was
dried, concentrated onto silica gel, and flash chromatographed (1 x 4 inches silica
gel). Gradient elution with ethyl acetate / hexane of from 1:1 to 100% ethyl acetate
followed by elution with 2 to 10 % ethanol/0.1 % ammonium hydroxide/ethyl acetate
gave recovered unweighed starting material. Continued elution with 15% methanol /
0.1% ammonium hydroxide/ethyl acetate gave 0.32 g of the title product as a clear
colorless oil which partially crystallized on standing. Trituration with ether gave
0.13 g (27%) of the title compound as white crystals: mp 141.5-144°C;
1H NMR δ 8.58 (br s, 1H), 8.04 (br s, 1H), 7.95 (dd,
J = 8, 1.5 Hz, 2H), 7.84 (d,
J = 9 Hz, 1H), 7.68 (dd,
J = 2, 9 Hz, 1H), 7.62-7.49 (m, 4H), 7.37 (t,
J = 8 Hz, 1H), 7.12 (d,
J = 7 Hz, 1H), 3.32-3.22 (m, 5H), 3.16 (br s, 3H), 2.40 (br s, 1H, exchanges with D
2O). HRMS m/e calculated for C
21H
21N
3O: 331.1680. Observed m/e: 331.1682.
Example 12
7-(4-Chlorobenzamido-1-(1-piperazinyl)-naphthalene
[0085] The title product of example 8 (1.69 g, 4.62 mmol) and 1,8-bis (dimethylamino)naphthalene
(3.47 g, 16.2 mmol) were dissolved in dichloroethane (160 mL) and chilled to 0°C.
1-Chloroethyl chloroformate (0.8 mL, 7.4 mmol) was added and the solution was refluxed
overnight. The mixture was concentrated and flash chromatographed on silica gel (2
x 3 inches). Elution with 10 to 25% ethyl acetate / hexane gave first an unweighed
impurities and then 1.56 g of a mixture of 1,8-bis (dimethylamino)naphthalene and
the urethane intermediate (1:1.2 ratio). The mixture was dissolved in methylene chloride
and extracted repeatedly with pH 5.8 buffer. The organic layer was dried over calcium
sulfate and concentrated to give 0.98g of base free intermediate urethane suitable
for subsequent reaction.
[0086] The intermediate was dissolved in methanol (40 mL) and refluxed 5 hours. The mixture
was concentrated and the residues were taken up in methylene chloride. The organic
phase was washed with 0.5 N NaOH and brine, dried over calcium sulfate and concentrated.
The residue was flash chromatographed on silica gel (1 x 2 inches). Elution with 5
to 15% methanol/0.1% ammonium hydroxide/ethyl acetate gave 0.667 g of oily solid.
This semi-solid recrystallized from methanol to give 0.54 g (32%) of the title compound
as tan crystals in two crops: mp 210-211 °C. HRMS m/e calculated for C
21H
20ClN
3O: 365.1290. Observed m/e: 365.1294.
Example 13
7-(1-Naphthylmethylamino)-1-(4-methyl-1-piperazinyl)-naphthalene
[0087] To a cold (-78°C) mixture of lithium aluminum hydride (0.012 g, 0.316 mmol) in THF
(5 mL) was added the product of example 5 (0.10 g, 0.256 mmol) all at once. The mixture
was allowed to warm to ambient temperature and stir 5 hours. The mixture was refluxed
overnight. The mixture was cooled to 0°C and additional lithium aluminum hydride (0.014
g, 0.368 mmol) was added and the mixture was refluxed 5 hours more. The mixture was
again cooled to 0°C and carefully quenched with water and the solvent was removed.
The residue was taken up in ethyl acetate, dried over sodium sulfate, concentrated,
and flash chromatographed on silica gel (1 x 2.5 inches). Elution with a gradient
of 50 to 85% ethyl acetate/hexane gave 0.05 g of title product. Recrystallization
from ether gave 0.018 g (18.5%) of title product as a white solid: mp 140-141 °C.
HRMS m/e calculated for C
26H
27N
3: 381.2199. Observed m/e: 381.2217.
Example 14
7-(Benzvlamino)-1 -(4-methyl-1-piperazinyl)-naphthalene
[0088] The title product of example 1 (0.12 g, 0.348 mmol) was dissolved in toluene (4 mL)
and borane-dimethyl sulfide (0.3 mL, 3 mmol) was added. The mixture was refluxed 3
hours and cooled. 6 N HCI and ethyl acetate were added and the mixture was refluxed
until all the solids had dissolved. The organic phase was separated and discarded.
The aqueous phase was made basic with 4 N NaOH and extracted with methylene chloride.
This organic phase was washed with brine, dried over calcium sulfate and concentrated.
The crude product was purified by flash chromatography on silica gel (0.5 x 4 inches).
Elution with 50% and then 75% ethyl acetate/hexane gave 0.053 g of product. This material
was further purified by trituration with hexane to provide 0.03 g, (26 %) of the title
product as a tan powder: mp 115-117°C;
1H NMR δ 7.64 (d,
J = 8.5 Hz, 1H), 7.46-7.24 (m, 6H), 7.14 (t,
J = 7.5 Hz, 1H), 7.07 (d,
J = 2.5 Hz, 1H), 7.00 (ss,
J = 1, 7.5 Hz, 1H), 6.94 (dd,
J = 2.5, 8.5 Hz, 1H), 4.50 (br s, 2H), 4.34 (br m, 1H), 3.01 (br s, 4H), 2.53 (br s,
4H), 2.38 (s, 3H). Analysis calculated for C
22H
25N
3•0.5 H
2O: C, 77.61; H, 7.70; N, 12.34. Found: C, 77.78; H, 7.48; N, 12.07.
Example 15
7-Trifluoroacetamido-1 -(4-methyl-1-piperazinyl)-naphthalene
[0089] A solution of 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.25 g, 1.04 mmol)
and triethylamine (0.15 mL, 1.14 mmol) in dry THF was chilled to 0°C and treated with
trifluoroacetic anhydride (0.16 mL, 1.14 mmol). The mixture was allowed to warm to
ambient temperature and stir overnight. Triethylamine (0.25 mL, 1.88 mmol) and trifluoroacetic
anhydride (0.16 mL, 1.14 mmol) were added and the solution was stirred another 24
hours. Triethylamine (0.15 mL, 1.14 mmol) was added and the solution was stirred 2
hours more. The solvent was removed at reduced pressure and the residue was taken
up in methylene chloride. The organic solution was washed with saturated sodium bicarbonate
and brine, then it was dried over calcium sulfate and concentrated. The product was
purified by silica gel flash chromatography (1 x 2 inches). Ethyl acetate/hexane gradient
elution of from 1:1 to 3:1 gave 0.15 g of oily product. Trituration with hexane gave
0.11 g (31%) of the title product. A sample recrystallized from methyl cyclohexane
was submitted for analysis: mp 159-160°C. HRMS m/e calculated for C
17H
18F
3N
3O: 337.1400. Observed m/e: 337.13867. Analysis calculated for C
17H
18F
3N
3O: C, 60.53; H, 5.38; N, 12.46. Found: C, 60.04; H, 5.27; N, 12.05.
Example 16
7-Acetamido-1-(4-methyl-1-piperazinyl)-naDhthalene
[0090] A solution of 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.238 g, 0.986 mmol)
and triethylamine (0.144 mL, 1.08 mmol) in acetonitrile (12 mL) was chilled to 0°C
and acetyl chloride (0.077 mL, 1.08 mmol) was added all at once. The mixture was heated
to reflux for 7 hours and cooled to room temperature. (TLC with 40% methanol/ethyl
acetate indicated that the reaction was complete.) The solvent was removed at reduced
pressure and the residue was taken up in methylene chloride. The organic solution
was extracted with saturated sodium bicarbonate and brine, then it was dried over
calcium sulfate and concentrated to a light tan solid (0.115 g). Trituration with
hexane gave 0.09 g (33%) of the title product as a tan solid: mp 173-177°C. A sample
recrystallized from ethyl acetate was submitted for analysis: mp 177-180°C. HRMS m/e
calculated for C
17H
21N
3O: 283.1682. Observed m/e: 283.1678.
Example 17
7-Hexanamido-1-(4-methyl-1-piperazinyl)-naphthalene
[0091] The title product was prepared following the procedure of example 16 from 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene
(0.182 g, 0.755 mmol) and triethylamine (0.201 mL, 1.51 mmol) and hexanoyl chloride
(0.211 mL, 1.51 mmol) in acetonitrile (10 mL) with an overnight reflux. The product
was purified by recrystallization from ethyl acetate/hexane to yield 0.097g (37%)
of the title compound: mp 144-146°C. Analysis calculated for C
21H
29N
3O: C, 74.30; H, 8.61; N, 12.38. Found: C, 73.91; H, 8.52; N, 12.22.
Example 18
7-(p-Toluenesulfonamido)-1-(4-methyl-1-piperazinyl)-naphthalene
[0092] A solution of 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.205 g, 0.85 mmol)
and triethylamine (0.124 mL, 0.935 mmol) in dry THF (3 mL) was chilled to 0°C and
para toluenesulfonyl chloride (0.178 g, 0.935 mmol) was added all at once. The mixture
was allowed to warm to room temperature and stirred overnight (TLC with 40% methanol/ethyl
acetate indicated that the reaction was complete.) The solvent was removed at reduced
pressure and the residue was taken up in methylene chloride. The organic solution
was extracted with saturated sodium bicarbonate and brine, then it was dried over
calcium sulfate and concentrated. Flash chromatography on silica gel (1 x 3 inches)
with ethyl acetate/hexane gradient elution of from 50% to 100% gave 0.21 g of a light
tan solid. The solid was further purified by two recrystallizations from ethyl acetate
to yield 0.07 g (20%) of the title product: mp 180-181.5°C. Analysis calculated for
C
22H
25N
3O
2S: C, 66.81; H, 6.37; N, 10.62. Found: C, 66.55; H, 6.31; N, 10.20.
Example 19
7-(Phenylaminocarbonylamino)-1-(4-methyl-1-piperazinyl)-naphthalene
[0093] 7-Amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.216 g, 0.896 mmol) and phenyl isocyanate
(0.222 g, 1.86 mmol) were combined in acetonitrile (14 mL) and refluxed overnight.
Phenyl isocyanate (0.106 g, 0.896 mmol) was added and the reaction was refluxed 2
hours more. Upon cooling a tan solid precipitated which was collected and recrystallized
from methanol/ethyl acetate to give 0.202 g (62%) of the title product; mp 213-214°C.
Analysis calculated for C
22H
24N
4O: C, 73.31; H, 6.71; N, 15.54. Found: C, 73.03; H, 6.55; N, 15.22.
Example 20
7-(Benzyloxycarbonylamino)-1-(4-methyl-1-piperazinyl)-naphthalene
[0094] 7-Amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.225 g, 0.933 mmol), benzyl chloroformate
(0.147 mL, 1.03 mmol), and potassium carbonate (0.142 g, 1.03 mmol) were combined
in a two phase mixture of methylene chloride (10 mL) and water (3 mL) and the mixture
was stirred at room temperature overnight. Benzyl chloroformate (0.147 mL, 1.03 mmol)
was added and the reaction was stirred 5 hours more. The reaction was diluted with
methylene chloride and the phases were separated. The organic layer was washed with
brine, dried over calcium sulfate and concentrated to a brown oil which was flash
chromatographed on silica gel (1 x 4 inches). Gradient elution with ethyl acetate/hexane
of from 50% to 100% followed by gradient ethanol/ethyl acetate elution of from 5%
to 10% gave 0.29 g of a brown foam. This residue was recrystallized from ethyl acetate
to give 0.095 g (27%) of the title product in two crops; mp 143-144°C. Analysis calculated
for C
23H
25N
3O
2: C, 73.58; H, 6.71; N, 11.19. Found: C, 73.46; H, 6.71; N, 11.05.
Example 21
7-[(2-Benzyloxycarbonylamino)-acetamido]-1-(4-methyl-1-piperazinyl)-naphthalene
[0095] N-benzyloxycarbonylglycine (0.69 g, 3.32 mmol) was dissolved in methylene chloride
(10 mL) and carbonyl diimidazole (0.54 g, 3.32 mmol) was added. The solution was stirred
for 2 hours; then 7-amino-1-(4-methyl-1-piperizinyl)-naphthalene (0.2 g, 0.83 mmol)
was added. The solution was stirred overnight. The reaction was extracted with saturated
aqueous potassium carbonate and brine, dried over calcium sulfate and concentrated
to give white crystals. Recrystallization from ethyl acetate gave 0.187 g (52 %) of
the title product as white crystals: mp 187-188°C. Analysis calculated for C
25H
28N
4O
3: C, 69.42; H, 6.52; N, 12.95. Found: C, 69.21; H, 6.50; N, 12.79.
Example 22
7-(Benzoylaminothiocarbonylamino)-1-(4-methyl-1-piperazinyl)-naphthalene
[0096] To a mixture of ammonium thiocyanate (0.376 g, 4.94 mmol) in acetone (5 mL) was added
benzoyl chloride (0.57 mL, 4.94 mmol) dropwise. The mixture (white precipitate) was
refluxed 45 minutes which resulted in a yellow heterogeneous solution. A solution
of 7-Amino-1-(4-methyl-1-piperazinyl)-naphthalene (1.0 g, 4.14 mmol) in acetone (25
mL) was added dropwise (10 mL acetone rinse also added). The mixture was refluxed
4 hours and allowed to stir overnight at ambient temperature. The mixture was concentrated
onto silica gel and flash chromatographed (2 x 3.5 inches). Gradient elution with
ethyl acetate/hexane of from 50% to 100% gave an unweighed forerun. Continued gradient
elution with 10 to 40% ethanol/ethyl acetate gave 1.3 g (77%) of title product as
a yellow foam which was suitable for use without further purification. The compound
was found to slowly decompose at room temperature. A sample recrystallized from ethyl
acetate/methylene chloride for analysis: mp 160-250°C.
1H NMR (DMSO
d6, D
2O) δ 8.74 (s, 1H), 7.97 (d,
J = 7.5 Hz, 1H), 7.91 (d,
J = 9 Hz, 1H), 7.70-7.51 (m, 5H), 7.42 (t,
J = 8 Hz, 1H), 7.12 (d,
J = 7 Hz, 1H), 3.11 (m, 4H), 2.79 (br s, 4H), 2.39 (s, 3H). HRMS m/e calculated for
C
23H
24N
4OS: 404.1661. Observed m/e: 404.1633.
Example 23
7-(Aminothiocarbonylamino)-1-(4-methyl-1-piperazinyl)-naphthalene
[0097] The title product of example 22 (1.09 g, 2.7 mmol) was slurried in ethanol (10 mL)
and a solution of 1.4 g NaOH in water (14 mL) was added. The mixture was refluxed
3 hours; then the ethanol was removed with a stream of nitrogen. The aqueous residue
was extracted with methylene chloride. The organic phase was washed with brine, dried
over calcium sulfate, and concentrated to leave 0.39 g (48%) of the title product.
A sample was recrystallized from acetonitrile for analysis: mp 194-195°C. Analysis
calculated for C
16H
20N
4S•CH
3CN•0.5 H
2O: C, 62.96; H, 6.67; N, 19.32. Found: C, 62.86; H, 6.71; N, 19.69.
Example 24
4-Benzyl-2-[-1-(4-methyl-1-piperazinyl)-7-naphthylamino]-thiazole
[0098] A mixture of the title product of example 23 (0.225 g, 0.75 mmol) and 1 -chloro-3-phenylacetone
(0.188 g, 1.12 mmol) in isopropanol (6 mL) was refluxed 3 hours. The solvent was removed
and the residue was taken up in methylene chloride. The organic phase was washed with
saturated aqueous sodium bicarbonate and brine, dried over calcium sulfate, and concentrated
onto silica gel for flash chromatography (1 x 3 inches). Gradient elution with 50%
to 100% ethyl acetate/hexane gave an unweighed forerun. Continued elution with ethyl
acetate gave 0.283 g of a yellow foam. Trituration with ethyl acetate gave 0.137 g
(44%) of the title product as yellow crystals: mp 157-160°C. Analysis calculated for
C
25H
26N
4S: C, 72.43; H, 6.32; N, 13.51. Found: C, 72.55; H, 6.51; N, 13.72.
Example 25
7-(3-Nitro-2-pyridinylamino)-1-(4-methyl-1-piperazinyl)-nephthalene
[0099] 7-Amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.247g, 1.02 mmol), 2-chloro-3-nitropyridine
(0.325 g, 2.05 mmol), and 4-dimethylaminopyridine (0.062 g, 0.51 mmol) were combined
in dry DMF (0.15 mL). The solution was refluxed 4 hours then 0.5 mL more DMF was added
and the mixture was allowed to stir at ambient temperature overnight. 2-Chloro-3-nitropyridine
(0.105 g, 0.69 mmol), and 4-dimethylaminopyridine (0.062 g, 0.51 mmol) were added
and the mixture was refluxed 2 hours more. The solvent was removed in vacuo and the
residue was taken up in methylene chloride. This organic phase was washed with 0.5
N sodium hydroxide and brine; then it was dried over calcium sulfate and concentrated
to a red oil which was flash chromatographed on silica gel (1 x 4 inches). Gradient
elution with 50% to 75% ethyl acetate/hexane followed by elution with 100% ethyl acetate
gave a dark colored oil which crystallized upon addition of ether (2 mL) to yield
0.19 g (51%) as a dark red solid: mp 127.5-129°C. Analysis calculated for C
20H
21N
5O
2: C, 66.10; H, 5.82; N, 19.27. Found: C, 66.04; H, 5.81; N, 19.02.
Example 26
7-(2,4-Dinitrophenylamino)-1-(4-methyl-1-piperazinyl)-naphthalene
[0100] A mixture of 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.05 g, 0.207 mmol)
and 2,4-dinitrochlorobenzene (0.75 g, 0.373 mmol) in dry DMF (2 mL) was refluxed 2
hours. The solvent was removed in vacuo and the residue was taken up in methylene
chloride. The organic phase was washed with saturated sodium bicarbonate and brine,
dried over calcium sulfate and concentrated. The residue was recrystallized from ether
to give 0.045g (54%) of the title compound: mp 153-154°C. Analysis calculated for
C
21H
21N
5O
4: C, 61.91; H, 5.20; N, 17.19. Found: C, 61:42; H, 5.10; N, 16.79.
Example 27
7-(5-Nitro-2-pyridylamino)-1-(4-methyl-1-piperazinyl)-naphthalene
[0101] A mixture of 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.212 g, 0.88 mmol),
5-nitro-2-chloropyridine (0.314 g, 1.98 mmol), and 4-dimethylaminopyridine (0.085
g, 0.7 mmol) in dry DMF (2 mL) was refluxed 8 hours. The solvent was removed in vacuo
and the residue was taken up in methylene chloride. The organic phase was washed with
saturated 0.5 N NaOH and brine, dried over calcium sulfate and concentrated. The residue
was flash chromatographed on silica gel (1 x 4 inches). Gradient elution with from
50% to 90% ethyl acetate/hexane gave an unweighed forerun. Continued elution with
ethyl acetate gave 0.136 g of orange oil. Recrystallization from isopropanol followed
by recrystallization from nitromethane gave 0.005 g (1.4%) of the title product as
orange crystals: mp 121-125°C. Analysis calculated for C
20H
21N
5O
2•H
2O: C, 62.98; H, 6.08; N, 18.36. Found: C, 62.86; H, 5.84; N, 18.13.
Example 28
7-(2-Nitrophenylamino)-1-(4-methyl-1-piperazinyl)-naphthalene
[0102] The title product was obtained following the procedure of example 27 by reacting
7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.225 g, 0.93 mmol), 2-fluoronitrobenzene
(0.255 g, 1.8 mmol), and 4-dimethylaminopyridine (0.167 g, 1.37 mmol) in dry DMF (5
mL) with an overnight reflux. The product was isolated by silica gel flash chromatography
and recrystallization from ethyl acetate/ether to yield 0.024g (7%) of the title compound
as orange crystals: mp 87-94°C;
1H NMR δ 9.70 (br s, 1 H), 8.26 (dd,
J = 1.5, 8.5 Hz, 1H), 8.07 (d,
J = 2 Hz, 1H), 7.87 (d,
J = 8.5 Hz, 1H), 7.57 (s,
J = 8 Hz, 1H), 7.44-7.32 9m, 4H), 7.16 (dd,
J = 1, 7.5 Hz, 1H), 6.82 (dd,
J = 2, 6.5, 8.5 Hz, 1H), 3.15 (br s, 4H), 2.70 (br s, 4H), 2.41 (s, 3H). HRMS m/e calculated
for C
21H
22N
4O
2: 362.1738. Observed m/e: 362.1736.
Example 29
7-(3-Amino-2-pyridylamino)-1-(4-methyl-1-piperazinyl)-naphthalene
[0103] To a slurry of 10% palladium on carbon (0.56 g) in ethanol (30 mL) was added the
title product from example 25 (3.38 g, 9.3 mmol) was dissolved in a mixture of ethanol
(20 mL), methanol (50 mL), and ethyl acetate (100 mL). The mixture was hydrogenated
at 50 psi for 3 hours. A total of 36 psi of H
2 was taken up (35 psi is theory). The mixture was filtered through celite and the
filter pad was rinsed well with ethyl acetate. The filtrate was concentrated to give
3.4 g (100%) of brown crystals which was an ethanolate of the title product which
was suitable for further reaction without purification. A sample recrystallized from
ethanol for analysis: mp 198-200°C. Analysis calculated for C
20H
23N
5: C, 72.04; H, 6.95; N, 21.00. Found: C, 71.72; H, 6.87; N, 20.84.
Example 30
7-(3-Benzamido-2-pyridylamino)-1-(4-methyl-1-piperazinyl)-naphthalene
[0104] The title product from example 29 (0.2 g, 0.6 mmol) and triethylamine (0.15 mL, 1.1
mmol) were dissolved in THF (8 mL) and the solution was chilled to 0°C. Benzoyl chloride
(0.09 mL, 0.78 mmol) was added and the mixture was stirred 24 hours at room temperature.
The solvent was removed and the residue was taken up in methylene chloride. The organic
phase was washed with 1N NaOH and brine; then it was dried through phase separating
paper and concentrated onto silica gel for flash chromatography (1 x 3.5 inches).
Elution with methylene chloride then 3% methanol/methylene chloride was not productive.
Continued elution with 6% methanol/methylene chloride gave first 0.108 g of an impurity
and second 0.128 g of product as a tan foam. The foam was further purified by recrystallization
from ethyl acetate to yield 0.078 g (30%) of the title product as tan crystals: mp
205-207°C. Analysis calculated for C
27H
27N
5O: C; 74.12; H, 6.22; N, 16.01. Found: C, 73.59; H, 5.93; N, 15.54.
Example 31
7-(3-Acetamido-2-pyridylamino)-1-(4-methyl-1-piperazinyl)-naphthalene
[0105] The title compound was prepared following the procedure of example 30 from the product
of example 29 (0.25 g, 0.75 mmol), acetyl chloride (0.045 mL, 0.80 mmol) and triethylamine
(0.11 mL, 0.803 mmol) in tetrahydrofuran (8 mL) with stirring at room temperature
for 3 hours. The product was isolated by flash chromatography and recrystallization
from methylene chloride to yield 0.18g (64%) of the title compound: mp 110-114°C (dec.).
1H NMR (DMSO
d6) δ 9.47 (s, 1H), 8.65 (d,
J = 1.5 Hz, 1H), 8.35 (s, 1H), 8.03 (dd,
J = 1.5, 5 Hz, 1H), 7.77-7.70 (m, 2H), 7.53 (dd,
J = 2, 9 Hz, 1H), 7.46 (d,
J = 8 Hz, 1H), 7.22 (t,
J = 8 Hz, 1H), 7.00 (d,
J = 7.5 Hz, 1H), 6.88 (dd,
J = 5, 8 Hz, 1H), 3.07 (br s, 4H), 2.63 (br s, 4H), 2.29 (s, 3H), 2.14 (s, 3H). HRMS
m/e calculated for C
22H
25N
5O: 375.2054. Observed m/e: 375.2023.
Example 32
1-(4-Methyl-1-piperazinyl)-7-(1-pyridotriazolo)-naphthalene
[0106] The title product from example 29 (0.219 g, 0.657 mmol) was dissolved in 5 % sulfuric
acid (1.5 mL) and chilled to 0°C. Sodium nitrite (0.048 g, 0.69 mmol) was dissolved
in water (0.25 mL) and added dropwise with a water rinse (2 x 0.25 mL). The mixture
was allowed to stir overnight. The reaction was poured onto ice and neutralized with
1 N NaOH. The aqueous mixture was extracted 3 times with methylene chloride and the
combined organic layer was washed with saturated sodium bicarbonate and brine. The
organic phase was dried through phase separating paper and concentrated to a brown
foam. The foam was recrystallized from methanol to afford 0.124 g (55%) of the title
product as tan crystals: mp 162-164°C.
1H NMR δ 9.28 (d,
J = 2 Hz, 1H), 8.82 (dd,
J = 1.5, 4.5 Hz, 1H), 8.52 (dd,
J = 1.5, 8.5 Hz, 1H), 8.39 (dd,
J = 2, 9 Hz, 1H), 8.05 (d,
J = 9 Hz, 1H), 7.63 (d,
J = 8 Hz, 1H), 7.52-7.45 (m, 2H), 7.19 (d,
J = 7.5 Hz, 1H), 3.27 (br s, 4H), 2.80 (br s, 4H), 2.45 (s, 3H). Analysis calculated
for C
20H
20N
6: C, 69.75; H, 5.85; N, 24.40. Found: C, 69.69; H, 5.72; N, 24.15.
Example 33
7-(Imidazol-2-ono-[4,5-b]pyridin-1-yl)-1-(4-methyl-1-piperazinyl)naphthalene
[0107] A mixture of the title product of example 29 (0.260 g, 0.78 mmol) and triethylamine
(0.21 mL, 1.56 mmol) in methylene chloride (12 mL) was chilled to 0°C and triphosgene
(0.09 g, 0.30 mmol) was added all at once. The mixture became homogeneous and was
stirred overnight at ambient temperature. Additional triphosgene (0.02 g, 0.07 mmol)
was added and the mixture was stirred 4 hours more. Saturated sodium bicarbonate was
added and the reaction was stirred 30 minutes to decompose any unreacted triphosgene.
The phases were separated and the organic layer was washed with brine and dried through
phase separating paper. The solution was concentrated and flash chromatographed on
silica gel (1 x 4 inches). Gradient elution with from 60% to 100% methylene chloride/hexane
was not productive. Continued elution with a gradient of from 2 to 4% methanol/methylene
chloride gave 0.032 g of an oil which was discarded. Further elution with a gradient
of 4 to 7% methanol/methylene chloride gave 0.23 g of crystalline solid product. The
solid was triturated with methylene chloride and filtered to afford 0.079 g (28%)
of the title product as a white powder: mp 260-262°C (dec.).
1H NMR (DMSO
d6) δ 11.44 (br s, 1H), 8.49 (d,
J = 1.5 Hz, 1H), 8.01 (d,
J = 9 Hz, 1H), 7.97 (dd,
J = 1.5, 5 Hz, 1H), 7.86 (dd,
J = 2, 9 Hz, 1H), 7.64 (d,
J = 8 Hz, 1H), 7.49-7.42 (m, 2H), 7.16-7.11 (m, 2H), 3.10 (br s, 4H), 2.58 (br s, 4H),
2.25 (s, 3H). HRMS m/e calculated for C
21H
21N
5O: 359.1742. Observed m/e: 359.1705. Analysis calculated for C
21H
21N
5O·H
2O: C, 68.46; H, 6.02; N, 19.01. Found: C, 68.38; H, 5.47; N, 18.66.
Example 34
1-(4-Methyl-1-piperazinyl)-7-(3-(3,3-dimethylformamidino)-2-pyridylamino)-naphthalene
[0108] To a solution of the title product of example 29 (0.453, 1.36 mmol) in dry dimethyl
formamide (5 mL) was added dimethyl formamide dimethyl acetal (5 mL, 35.4 mmol). The
resulting solution was refluxed 4 hours and allowed to stir at room temperature overnight.
The solvent was removed in vacuo and the residue was flash chromatographed on silica
gel (1 x 7 inches). Gradient elution with from 50 to 100% of ethyl acetate / hexane
then a gradient of from 1 to 6% ethanol/ethyl acetate gave 0.352 g (67 %) of the title
product as a yellow foam which was suitable for further reaction. A sample was recrystallized
from ether gave the bright yellow crystalline title product for analysis: mp 108-111
°C.
1H NMR δ 9.00 (d,
J = 2 Hz, 1H), 8.03-7.97 (m, 2H), 7.73 (d,
J = 9 Hz, 1H), 7.53-7.42 (sym m, 2H), 7.23 (t,
J = 8 Hz, 1H), 7.05-6.98 (sym m, 2H), 6.69 (dd,
J = 5, 7.5 Hz, 1H), 3.24 (br s, 4H), 3.13 (br s, 6H), 2.80 (br s, 4H), 2.46 (s, 3H).
Analysis calculated for C
23H
28N
6: C, 71.10; H, 7.26; N, 21.63. Found: C, 71.16; H, 7.17; N, 21.59.
Example 35
7-(Imidazolo[4,5-b]pyridin-1-yl)-1-(4-methyl-1-piperazinyl)-naphthalene
[0109] The title product of example 34 (0.25 g, 0.64 mmol) was slurried in toluene and a
catalytic amount of para toluenesulfonic acid (a couple of crystals) was added. The
mixture was refluxed 4 hours, cooled and concentrated. The residue was taken up in
methylene chloride and washed with saturated sodium bicarbonate and brine; then it
was dried over calcium sulfate and concentrated to a yellow oil (0.165 g). The oil
was further purled by recrystallization from ether to afford 0.057 g (26 %) of the
title product as yellow crystals: mp 107-112°C;
1H NMR δ 8.65 (d,
J = 2 Hz, 1H), 8.52-8.48 (m, 2H), 8.21 (dd,
J = 1.5, 8 Hz, 1H), 8.04 (d,
J = 8.5 Hz, 1H), 7.87 (dd,
J = 2, 8 Hz, 1H), 7.64 (d,
J = 8 Hz, 1H), 7.46 (t,
J = 8 Hz, 1), 7.36 (dd,
J = 5, 8 Hz, 1H), 7.20 (d,
J = 7 Hz, 1 H), 3.24 (br s, 4H), 2.75 (br s, 4H), 2.43 (s, 3H). Analysis calculated
for C
21H
21N
5•H
2O: C, 71.57; H, 6.29; N, 19.87. Found: C, 71.32; H, 6.32; N, 19.44.
Example 36
7-(Imidazolo[4,5-b]pyridin-1-yl)-1-(4-methyl-1-piperazinyl)-naphthalene
[0110] The title product of example 29 (0.217 g, 0.65 mmol) was dissolved in acetic acid
(3 mL) and diethyl ethoxymethylenemalonate (0.138 mL, 0.68 mmol) was added. The mixture
was stirred at 55°C for 5 hours. The reaction was cooled and diethyl ethoxymethylenemalonate
(0.04 mL, 0.2 mmol) was added. The reaction was heated to 100°C overnight. The solvent
was removed in vacuo and the residue was taken up in chloroform and neutralized with
ice cold saturated sodium bicarbonate and washed with brine. The organic layer was
dried over calcium sulfate, concentrated and flash chromatographed on silica gel (1
x 2.5 inches). Elution with methylene chloride and then 2% methanol/0.05% ammonium
hydroxide/methylene chloride gave an unweighed forerun. Continued elution with 4%
methanol/0.05% ammonium hydroxide/methylene chloride gave a tan oil which crystallized
upon scratching. The crystals were collected, rinsed with ether, and dried to afford
0.066 g, (30%) of the title compound: mp 107-112°C;
1H NMR δ 8.65 (d,
J = 2 Hz, 1H), 8.52-8.48 (m, 2H), 8.21 (dd,
J = 1.5, 8 Hz, 1H), 8.04 (d,
J = 8.5 Hz, 1H), 7.87 (dd,
J = 2, 8 Hz, 1H), 7.64 (d,
J = 8 Hz, 1H), 7.46 (t,
J = 8 Hz, 1), 7.36 (dd,
J = 5, 8 Hz, 1H), 7.20 (d,
J = 7 Hz, 1H), 3.24 (br s, 4H), 2.75 (br s, 4H), 2.43 (s, 3H).
Example 37
7-(Benzimidazol-1-yl)-1-(4-methyl-1-piperazinyl)-naphthalene
[0111] To a slurry of 10 % palladium on carbon (0.022 g) in ethanol (5 mL) was added the
product of example 28 (0.091 g, 0.25 mmol in 25 mL of dioxane). Methanol (5 mL) was
added and the mixture was hydrogenated at 50 psi for 6 hours. The reaction was filtered
through celite and concentrated to afford a residue which was used without purification.
[0112] The above residue was dissolved in acetic acid (1.5 mL) and diethyl ethoxymethylenemalonate
(0.058 mL, 0.29 mmol) was added. The mixture was stirred at 95°C for 2 hours. The
mixture was chilled to 0°C and neutralized with 1 N NaOH. The mixture was extracted
with methylene chloride and this organic layer was washed with brine, dried through
phase separating paper, and concentrated for flash chromatography on silica gel (1
x 2 inches). 50 to 100% ethyl acetate/hexane gradient elution was not productive.
Continued elution with 1 and 2% ethanol/ethyl acetate gave an unweighed forerun. Further
elution with a gradient of from 4 to 15% ethanol/ethyl acetate gave 0.083 g of a brown
oil. The oil was recrystallized from ether to yield 0.039 g (47%) of the title compound
as tan crystals: mp 148-150°C.
1H NMR δ 8.35 (d,
J = 2 Hz, 1H), 8.25 (s, 1H), 8.04 (d,
J = 8.5 Hz, 1H), 7.94 (sym m, 1H), 7.69-7.60 (m, 3H), 7.52 (t,
J = 8 Hz, 1H), 7.38 (sym m, 2H), 7.24 (d,
J = 7.5 Hz, 1H), 3.19 (br s, 4H), 2.70 (br s, 4H), 2.40 (s, 3H). HRMS m/e calculated
for C
22H
22N
4: 342.1840. Observed m/e: 342.1863.
Example 38
7-(3-Hydroxy-3-methyl-1-butynyl)-1-(4-methyl-1-piperazinyl)-naphthalene p-toluene
sulfonate
[0113] 7-trifluoromethylsulfonyloxy-1-(4-methyl-1-piperazinyl)-naphthalene (0.285 g, 0.761
mmol), 3-hydroxy-3-methylbutyne (0.12 mL, 1.24 mmol), triethylamine (0.52 mL, 3.73
mmol), and bis (triphenylphosphine) palladium chloride (0.03 g, 0.04 mmol) were combined
in dry dimethyl formamide (3 mL) and heated to 70 to 80°C. After 40 min the reaction
was cooled and poured into 30 mL of 1 N aqueous lithium chloride and extracted with
ether (3 x 15 mL). The combined ether layer was washed with water and brine; then
it was dried over magnesium sulfate and concentrated to an orange oil. The oil was
purified by flash chromatography on silica gel (1 x 6 inches). Elution with a gradient
of ethyl acetate and hexane followed by 100% ethyl acetate gave 0.15 g of orange oily
product (65%). The oil was dissolved in ether (5 mL) and p-toluene sulfonic acid (0.093
g, 0.489 mmol in ether) was added. An orange solid formed which was collected, rinsed
well with ether and ethyl acetate. Recrystallization from ethanol/ether gave 0.113
g (30%) of the title product as a dark orange solid; mp 194.5-195.5°C.
13C NMR (DMSO d
6) δ 147.46, 145.70, 137.86, 133.54, 128.99, 128.66, 128.17, 127.75, 126.90, 125.59,
125.53, 124.23, 120.07, 116.59, 96.66, 81.06, 63.78, 53.02, 42.33, 31.70, 20.80.
Example 39
7-(2-Ethylsulfonyl)ethenvl-1-(4-methyl-1-piperazinyl)-naphthalene (L) tartrate
[0114] The title product was prepared following the procedure of example 1 from 7-trifluoromethylsulfonyloxy-1-(4-methyl-1-piperazinyl)-naphthalene
(0.25 g, 0.67 mmol), 2-ethylsulfonyl-1-chloroethane (0.11 g, 0.7 mmol), triethylamine
(0.47 mL, 3.37 mmol), and bis (triphenylphosphine) palladium chloride (0.025 g, 0.036
mmol) in dimethyl formamide (10 mL), the reaction being carried out at reflux for
4 hours followed by stirring at ambient temperature overnight. The product was purified
by flash chromatography on silica gel (1 x 4 inches). Elution with 50 and 75% ethyl
acetate/hexane gave recovered starting material (0.07 g, 28%). Continued elution with
ethyl acetate and then 10% methanol/ethyl acetate gave 0.06 g (26%) of product;
1H NMR δ 8.31 (d,
J = 1 Hz, 1H), 7.85-7.77 (m, 2H), 7.62-7.44 (m, 3H), 7.15 (dd,
J = 1.3, 7.2 Hz, 1H), 6.90 (d,
J = 15.5 Hz, 1H), 3.19-3.10 (m, 6H), 2.75 (m, 4H), 2.45 (s, 3H), 1.42 (t,
J = 7.5 Hz, 3H). The (L) tartrate salt was formed in methanol with 1 equivalent of
(L) tartaric acid. Concentration of the methanolic solution and recrystallization
from ethyl acetate/ether gave 0.035 g of light yellow hygroscopic solid title product:
mp 110-120°C. Analysis calculated for C
19H
24N
2O
2S•C
4H
6O
6•2H
2O: C, 52.07; H, 6.46; O, 5.27. Found: C, 51.70; H, 5.89; N, 5.11.
Example 40
7-(4-Chlorobenzyloxy)-1-(4-methyl-1-piperazinyl)-naphthalene
[0115] 7-Hydroxy-α-tetralone (1.0 g, 6.17 mmol), 4-chlorobenzyl bromide (1.27 g, 6.18 mmol),
and potassium carbonate (1.7 g, 12.3 mmol) were combined in acetone (50 mL) and refluxed
4.5 hours. The mixture was cooled to room temperature, filtered and concentrated to
a yellow solid. This material was recrystallized from ether to yield 1.28 g (72%)
of 7-(4-chlorobenzyloxy)-a-tetralone as a light yellow solid: mp 91-92°C. Analysis
calculated for C
17H
15ClO
2: C, 71.20; H, 5.27. Found: C, 71.22; H, 5.20.
[0116] The product of the above reaction (1.0 g, 3.49 mmol) was combined with N-methylpiperazine
(1.25 mL, 11.27 mmol) in dry tetrahydrofuran (THF, 50 mL) and chilled to -78°C. A
solution of titanium tetrachloride (0.52 mL, 4.74 mmol) in methylene chloride (2 mL)
was added dropwise over 3 minutes resulting in a milky green solution. The reaction
was warmed to ambient temperature and stirred 2.5 hours; then it was quenched with
50 mL of a 2/1 mixture of water and ammonium hydroxide. The THF was removed with a
stream of nitrogen. The residual aqueous phase was extracted with ethyl acetate (2x).
The organic extracts were dried over magnesium sulfate and concentrated in vacuo to
give 1.22 g (95%) of 7-(4-chlorobenzyloxy)-1-(4-methyl-1-piperazinyl)-3,4-dihydronaphthalene
as a light yellow solid: mp 115-116.5°C. Analysis calculated for C
22H
25ClN
2O: C, 71.63; H, 6.83; N, 7.59. Found: C, 71.54; H, 6.56; N, 6.95.
[0117] The product of the above reaction (1.2 g) was combined with 10% palladium on carbon
(0.62 g, predried) in dry toluene (50 mL) and refluxed. After several hours of reflux,
0.5 g more catalyst was added and the reaction was further refluxed overnight. The
reaction was cooled to room temperature and filtered through celite. The pad was rinsed
well with ethyl acetate. Concentration yielded an orange oil which was purified by
flash chromatography on silica gel (1 x 4 inches). Elution with 50 % ethyl acetate/hexane
gave unweighed recovered starting material. Continued elution as above gave 0.54 g
of 7-hydroxy-1-(4-methyl-1 -piperazinyl)-naphthalene. Further elution with ethyl acetate
gave the title product (0.06 g). The title product was recrystallized from ether to
afford 0.033 g (2.7%) of light yellow solid: mp 111.5-112°C. Analysis calculated for
C
22H
23ClN
2O: C, 72.02; H, 6.32; N, 7.64. Found: C, 71.92; H, 6.27; N, 7.69.
Example 41
7-(3-Methylaminosulfonylphenyl)-1-(4-methyl-1-piperazinyl)naphthalenen
[0118] 7-Trimethylstannyl-1-(4-methyl-1-piperazinyl)-naphthalene (0.25 9, 0.67 mmol), 3-methylaminosulfonyl-1-bromobenzene
(0.18 g, 0.72 mmol), triethylamine (0.45 mL, 3.23 mmol), lithium chloride (0.088 g,
2.07 mmol), and bis (triphenylphosphine) palladium chloride (0.025 g, 0.036 mmol)
were combined in DMF (12.5 mL) and heated to 110 to 110°C for 45 minutes. The reaction
was cooled to room temperature and 1 N aqueous lithium chloride (20 mL) was added.
The mixture was extracted with ether (2x). The combined organic layer was washed with
1 N lithium chloride and brine; then it was dried over magnesium sulfate and concentrated
to an orange oil. Flash chromatography on silica gel (1 x 6 inches) with an ethyl
acetate/hexane gradient of from 50 to 75% followed by continued elution with ethyl
acetate and finally 5% methanol/ethyl acetate 0.11 g (42%) of the title product. The
sample was recrystallized from ethyl acetate for analysis: mp 147.5-148°C. Analysis
calculated for C
22H
25N
3O
2S: C, 66.81; H, 6.31; N, 10.62. Found: C, 66.32; H, 6.16; N, 10.41.
Example 42
7-(3-Methylsulfonylaminophenyl)-1-(4-methyl-1-piperazinyl)-naphthalene
[0119] The title product was prepared following the procedure of example 41 from 7-trimethylstannyl-1-(4-methyl-1-piperazinyl)-naphthalene
(0.25 g, 0.67 mmol), 3-methylsulfonylamino-1 -bromobenzene (0.18 g, 0.72 mmol), triethylamine
(0.45 mL, 3.23 mmol), lithium chloride (0.088 g, 2.07 mmol), and bis (triphenylphosphine)
palladium chloride (0.025 g, 0.036 mmol) in DMF (12.5 mL) with a heating time of 1.5
hours. The product was obtained in 35% yield. A sample was obtained by recrystallization
from ethyl acetate for analysis: mp 100-101°C. Analysis calculated for C
22H
25N
3O
2S•1.5 H
2O: C, 62.54; H, 6.68; N, 9.94. Found: C, 62.70; H, 6.46; N, 9.89.
Example 43
7-Benzoyl-1-(4-methyl-1-piperazinyl)naphthalene
[0120] 7-Trimethylstannyl-1-(4-methyl-1-piperazinyl)-naphthalene (0.1 g, 0.27 mmol), benzoyl
chloride (0.031 mL, 0.27 mmol) and bis (acetonitrile) palladium chloride (0.007 g,
0.027 mmol) were combined in chloroform (5 mL) and heated to 60 to 65°C for 15 minutes.
The reaction was cooled to room temperature and saturated aqueous ammonium chloride
(10 mL) and chloroform (10 mL) were added. Phases were separated and the organic layer
was washed with brine, dried over magnesium sulfate, and concentrated to a milky oil.
The oil was purified by flash chromatography on silica gel (1 x 6 inches), the product
eluting with 5% methanol/ethyl acetate as a yellow oil (0.07 g, 79%). The oil was
crystallized from ether to obtain a bright yellow solid: mp 124-124.5°C. Analysis
calculated for C
22H
22N
2O: C, 79.97; H, 6.71; N, 8.48. Found: C, 79.74; H, 6.69; N, 8.46.
Example 44
7-(α-Hydroxybenzyl)-1-(4-methyl-1-piperazinyl)-naphthalene
[0121] The title product of example 43 (0.121 g, 0.366 mmol) was dissolved in ethanol (3
mL) and sodium borohydride (0.025 g, 0.66 mmol) was added. The mixture was stirred
1 hour at ambient temperature, then it was concentrated at reduced pressure at 40°C.
The residue was partitioned between ethyl acetate and water and the phases were separated.
The organic layer was washed with water and brine; then it was dried over magnesium
sulfate and concentrated to a light yellow oil. The oil was purified by flash chromatography
on silica gel (1 x 4 inches). Elution with 50% ethyl acetate/hexane removed a fast
moving component which was not identified. Continued elution with ethyl acetate gave
0.066 mg of the title product as a light tan oil which solidified. This solid was
recrystallized from chloroform/ether to afford 0.033 mg (27%) of the title product
as a light tan solid: mp 162.5-163°C. Analysis calculated for C
22H
24N
2O•0.25 H
2O: C, 78.42; H, 7.33; N, 8.31. Found: C, 78.52; H, 7.06; N, 8.31.
Example 45
7-(Diphenylhydroxymethyl)-1-(4-methyl-1-piperazinyl)-naphthalene
[0122] The title product of example 43 (0.072 g, 0.218 mmol) was dissolved in dry THF (10
mL) and chilled to 0°C. Phenyl magnesium bromide (3 M in ether, 0.08 mL, 0.24 mmol)
was added dropwise. The mixture fumed greenish and then returned to a yellow color.
The reaction was allowed to warm to room temperature for 30 minutes and then refluxed
for 45 minutes. Additional phenyl magnesium bromide (0.1 mL, 0.26 mmol) was added
and the mixture was refluxed 1 hour more. Saturated aqueous ammonium chloride was
added and the mixture was extracted with ethyl acetate. The organic phase was washed
with brine, dried over magnesium sulfate and concentrated to a light yellow oil. The
product was purified by silica gel flash chromatography (1 x 6 inches). Elution with
50% ethyl acetate/hexane followed by ethyl acetate gave 0.082 g (92%) of the title
product. A sample was recrystallized from chloroform/ether for analysis: mp 217.5-218.5°C.
Analysis calculated for C
28H
28N
2O•0.5 H
2O: C, 80.54; H, 7.00; N, 6.71. Found: C, 80.47; H, 6.63; N, 6.78.
Example 46
7-(p-Biphenyl)-1-(4-methyl-1-piperazinyl)-naphthalene
[0123] The title product was prepared following the procedure of example 41 from 7-trimethylstannyl-1-(4-methyl-1-piperazinyl)-naphthalene
(0.25 g, 0.67 mmol), 4-bromobiphenyl (0.17 g, 0.73 mmol), triethylamine (0.45 mL,
3.23 mmol), lithium chloride (0.088 g, 2.07 mmol), and bis (triphenylphosphine) palladium
chloride (0.025 g, 0.036 mmol) in DMF (12.5 mL) with a heating time of 1 hour at 100
to 115°C. The product obtained was 0.14 g (56%) in yield. A sample was obtained by
recrystallization from ether/hexane for analysis: mp 138.5-139.5°C. Analysis calculated
for C
27H
26N
2: C, 85.67; H, 6.92; N, 7.40. Found: C, 85.12; H, 6.97; N, 7.44.
Example 47
7-(3-Methoxycarbonylphenyl)-1-(4-methyl-1-piperazinyl)-naphthalene
[0124] The title product was prepared following the procedure of example 41 from 7-trimethylstannyl-1-(4-methyl-1-piperazinyl)-naphthalene
(0.25 g, 0.67 mmol), 3-methoxycarbonyl-1-bromobenzene (0.16 g, 0.74 mmol), triethylamine
(0.45 mL, 3.23 mmol), lithium chloride (0.088 g, 2.07 mmol), and bis (triphenylphosphine)
palladium chloride (0.025 g, 0.036 mmol) in DMF (12.5 mL) with a heating time of 1.5
hours at 120 to 130°C. The product obtained was 0.15 g (63%) in yield as an oil which
was converted to a hydrochloride salt with HCl gas in ether. The solid was collected
under a nitrogen atmosphere and recrystallized from chloroform/ether for analysis:
mp 201-203°C;
13C NMR δ 167.05, 147.37, 141.78, 137.80, 134.08, 131.87, 130.89, 129.57, 129.07, 128.63,
128.47, 126.28, 125.76, 125.02, 120.59, 116.85, 54.30, 52.33, 49.75, 43.70.
Example 48
7-(3-Fluorophenyl)-1-(4-methyl-1-piperazinyl)-naphthalene
[0125] The title product was prepared following the procedure of example 41 from 7-trimethylstannyl-1-(4-methyl-1-piperazinyl)-naphthalene
(0.25 g, 0.67 mmol), 3-fluoro-1-bromobenzene (0.13 g, 0.74 mmol), triethylamine (0.45
mL, 3.23 mmol), lithium chloride (0.088 g, 2.07 mmol), and bis (triphenylphosphine)
palladium chloride (0.025 g, 0.036 mmol) in DMF (12.5 mL) with a heating time of 2
hours at 120 to 130°C. The product obtained was 0.13 g (59%) in yield. A sample was
obtained by recrystallization from ether/hexane for analysis: mp 116-116.5°C. Analysis
calculated for C
22H
21FN
2: C, 79.49; H, 6.37; N, 8.43. Found: C, 79.07; H, 6.46; N, 8.66.
Example 49
7-(Benzyloxy)-1-(4-methyl-1-piperazinyl)-naphthalene
[0126] 7-Hydroxy-
α-tetralone (1.0 g, 6.17 mmol), benzyl bromide (0.80 mL, 6.73 mmol), and potassium
carbonate (1.7 g, 12.3 mmol) were combined in acetone (50 mL) and refluxed 22 hours.
The mixture was cooled to room temperature, filtered and concentrated at reduced pressure.
The residue was partitioned between ethyl acetate and 1 N sodium hydroxide. The phases
were separated and the organic layer was washed with water and brine; then it was
dried over magnesium sulfate and concentrated to a pale yellow solid. The material
was recrystallized from ether/hexane to yield 0.80 g (51%) of 7-benzyloxy-o-tetralone
as a cream solid: mp 84-84.5°C. Analysis calculated for C
17H
16O
2: C, 80.93; H, 6.39. Found: C, 80.39; H, 6.11.
[0127] The product of the above reaction (0.75 g, 2.97 mmol) was combined with N-methylpiperazine
(1.06 mL, 9.56 mmol) In dry tetrahydrofuran (THF, 50 mL) and chilled to -78°C. A solution
of titanium tetrachloride (0.44 mL, 4.01 mmol) in methylene chloride (2 mL) was added
dropwise over 3 minutes resulting in a milky green solution. The reaction was warmed
to ambient temperature and stirred overnight; then it was quenched with 50 mL of a
2/1 mixture of water and ammonium hydroxide. The THF was removed with a stream of
nitrogen. The residual aqueous phase was extracted with ethyl acetate (2 x). The organic
extracts were dried over magnesium sulfate and concentrated in vacuo to give 0.93
g (94%) of 7-benzyloxy-1-(4-methyl-1-piperazinyl)-3,4-dihydronaphthalene as an orange
oil which was suitable for use without further purification.
1H NMR δ 7.48-7.28 (m, 5H), 7.08-7.05 (m, 2H), 6.79 (dd,
J = 2.7, 8.2 Hz, 1H), 5.30 (t,
J = 4.7 Hz), 5.10 (s, 2H), 2.84 (br s, 4H), 2.64-2.50 (t,
J = 7.5 Hz overlapping with br s centered at δ 2.54, 6H total), 2.37 (s, 3H), 2.25-2.17
(m, 2H).
[0128] The product of the above reaction (0.93 g, 2.78 mmol) was combined with 10% palladium
on carbon (0.65 g, predried) in dry toluene (30 mL) and refluxed overnight. The reaction
was cooled to room temperature and filtered through celite. The pad was rinsed well
with ethyl acetate. Concentration yielded a yellow oil which was purified by flash
chromatography on silica gel (1 x 4 inches). Elution with 50% ethyl acetate/hexane
gave unweighed recovered starting material. Continued elution with 75% ethyl acetate/hexane
gave 0.18 g of 7-benzyloxy-1-(4-methyl-1-piperazinyl)-naphthalene as a colorless oil.
Recrystallization from ether gave 0.09 g (9.8%) of the tile product as a white solid:
mp 81.5-82.5°C. Analysis calculated for C
22H
24N
2O: C, 79.48; H, 7.28; N, 8.43. Found: C, 79.29; H, 7.41; N, 8.30. Further elution
with ethyl acetate gave 0.47 g of 7-hydroxy-1-(4-methyl-1-piperazinyl)-naphthalene.
Example 50
7-(3,4-Dichlorobenzyloxy)-1-(4-methyl-1-piperazinyl)-naphthalene
[0129] 7-Hydroxy-α-tetralone (1.0 g, 6.17 mmol), 3,4-dichlorobenzyl bromide (1.48, 6.18
mmol), and potassium carbonate (1.7 g, 12.3 mmol) were combined in acetone (50 mL)
and refluxed 21.5 hours. The mixture was cooled to room temperature, filtered and
concentrated at reduced pressure. The reside was partitioned between ethyl acetate
and 1N sodium hydroxide. The phases were separated and the organic layer was washed
with water and brine; then it was dried over magnesium sulfate and concentrated to
a pale yellow solid. This material was recrystallized from ether to yield 1.04 g (53%)
of 7-(3,4-dichlorobenzyloxy-α-tetralone as a fluffy white solid: mp 122.5-123°C. Analysis
calculated for C
17H
14Cl
2O
2: C, 63.57; H, 4.39. Found: C, 63.36; H, 4.21.
[0130] The product of the above reaction (0.90 g, 2.8 mmol) was combined with N-methylpiperazine
(1.0 mL, 9.01 mmol) in dry tetrahydrofuran (THF, 50 mL) and chilled to -78°C. A solution
of titanium tetrachloride (0.42 mL, 3.83 mmol) in methylene chloride (2 mL) was added
dropwise over 3 minutes resulting in a milky green solution. The reaction was warmed
to ambient temperature and stirred overnight; then it was quenched with 50 mL of a
2/1 mixture of water and ammonium hydroxide. The THF was removed with a stream of
nitrogen. The residual aqueous phase was extracted with ethyl acetate (2x). The organic
extracts were dried over magnesium sulfate and concentrated in vacuo to give 1.08
g (96%) of 7-(3,4-dichlorobenzyloxy-1-(4-methyl-1-piperazinyl)-3,4-dihydronaphthalene
as a yellow oil which was suitable for use without further purification.
1H NMR δ 7.55 (d,
J=2 Hz, 1H), 7.45 (d,
J=8.2 Hz, 1H), 7.29-7.25 (m, 1H), 7.07 (d,
J=8.2 Hz, 1H), 7.00 (d,
J=2.7 Hz, 1H), 6.75 (dd,
J=2.7, 8.2 Hz, 1H), 5.30 (t,
J=4.7 Hz, 1H), 5.05 (s, 2H), 2.80 (br s, 4H), 2.63-2.43 (m, 6H), 2.36 (s, 3H), 2.30-2.16
(m, 2H).
[0131] The product of the above reaction (1.08 g, 2.68 mmol) was combined with 10% palladium
on carbon (0.65 g, predried) in dry toluene (30 mL) and refluxed overnight. The reaction
was cooled to room temperature and filtered through celite. The pad was rinsed well
with ethyl acetate. Concentration yielded a brown oil which was purified by flash
chromatography on silica gel (1 x 4 inches). Elution with 75% ethyl acetate/hexane
gave an unweighted forerun. Continued elution with ethyl acetate gave 0.22 g of light
yellow solid. Recrystallization from ether gave 0.148 g (14%) of the title product
as a straw colored solid: mp 113-114°C. Analysis calculated for C
22H
22Cl
2N
2 O: C, 65.84; H, 5.53; N, 6.98. Found: C, 66.18; H, 5.63; N, 7.02.
Example 51
7-(4-Trifluoromethylbenzyloxy)-1-(4-methyl-1-piperazinyl)-naphthalene
[0132] To a mixture of 7-hydroxy-1-(4-methyl-1-piperazinyl)-naphthalene (0.20 g, 0.83 mmol),
triphenylphosphine (0.32 g, 1.22 mmol), and 4-trifluoromethylbenzyl alcohol (0.17
mL, 1.26 mmol) in dry THF (4 mL) was added diethyl azodicarboxylate in THF (1 mL).
The mixture was stirred overnight at ambient temperature; then it was concentrated
at reduced pressure. The residue was partitioned between ethyl acetate and 1 N sodium
hydroxide. The organic layer was washed with water and brine; then it was dried over
magnesium sulfate and concentrated onto silica gel for flash chromatographic purification
(1 x 6 inches). Elution with 75% ethyl acetate/hexane gave 0.24 g (72%) of the title
compound as a nearly colorless oil. The oil was treated with HCI in ether to form
the hydrochloride salt (0.23 g) which was recrystallized from chloroform/ether to
give 0.14 g of a white solid thereof: mp 205-206°C. Analysis calculated for C
23H
23F
3N
2O•HCl•0.25 H
2O: C, 62.58; H, 5.59; N, 6.35. Found: C, 62.59; H, 5.63; N, 6.40.
Example 52
7-Benzoyloxy-1-(4-methyl-1-piperazinyl)-naphthalene
[0133] A mixture of 7-hydroxy-1-(4-methyl-1-piperazinyl)-naphthalene (0.065 g, 0.268 mmol)
and benzoyl chloride (0.035 mL, 0.302 mmol) in methylene chloride (1 mL) and saturated
sodium bicarbonate (1 mL) was stirred at room temperature. After several hours, a
second equivalent of benzoyl chloride was added with continued stirring overnight.
The reaction was diluted with ethyl acetate and the phases were separated. The organic
layer was washed with 1 N sodium hydroxide, water and brine; then it was dried over
magnesium sulfate and concentrated to an oil which solidified (0.065 g, 69%). A sample
recrystallized from ether/hexane as a light pink solid was submitted for analysis:
mp 82-82.5°C. Analysis calculated for C
22H
22N
2O
2•0.25 H
2O: C, 75.30; H, 6.46; N, 7.98. Found: C, 75.51; H, 6.29; N, 7.97.
Example 53
7-(4-Chlorobenzoyloxy)-1-(4-methyl-1-piperazinyl)-naphthalene
[0134] The title product was obtained following the procedure of example 30 from 7-hydroxy-1-(4-methyl-1-piperazinyl)-naphthalene
(0.065 g, 0.268 mmol) and 4-chlorobenzoyl chloride (0.035 mL, 0.275 mmol) in methylene
chloride (1 mL) and saturated sodium bicarbonate (1 mL) with a second equivalent of
4-chlorobenzoyl chloride added after several hours of stirring at room temperature.
The title product was obtained in a yield of 0.058 g (57%) after recrystallization
from ether/hexane: mp 110-111°C. Analysis calculated for C
22H
21ClN
2O
2: C, 69.38; H, 5.56; N, 7.36. Found: C, 69.31; H, 5.61; N, 7.35.
Example 54
7-(3-Chlorobenzyloxy)-1-(4-methyl-1-piperazinyl)-naphthalene
[0135] A mixture of 3-chlorobenzyl bromide (1.27 g, 6.18 mmol), 7-hydroxy-
a-tetralone (1.0 g, 6.17 mmol), and potassium carbonate (1.7 g, 12.3 mmol) in acetone
(30 mL) was refluxed overnight. The reaction was cooled, filtered, and concentrated
at reduced pressure. The residue was partitioned between ethyl acetate and 1 N sodium
hydroxide. The organic phase was washed with water and brine, dried over magnesium
sulfate, and concentrated to a yellow solid. Recrystallization from ether/hexane gave
0.87 g (49%) of 7-(3-chlorobenzyloxy)-α-tetralone as a cream colored solid: mp 77-78°C.
Analysis calculated for C
17H
15ClO
2: C, 71.20; H, 5.27. Found: C, 71.25; H, 5.09.
[0136] A solution of 7-(3-chlorobenzyloxy)-α-tetralone (0.8 g, 2.79 mmol) and 1-methylpiperazine
(1.0 mL, 4.0 mmol) in dry THF (50 mL) was cooled to -78°C and treated with titanium
tetrachloride (0.42 mL, 3.83 mmol) in methylene chloride (2 mL). The reaction was
stirred 10 minutes at -78°C, then warmed to room temperature and stirred overnight.
The mixture was quenched with 50 mL of 5 N ammonia and extracted with ethyl acetate
(2x). This combined organic layer was dried over magnesium sulfate and concentrated
to a colorless oil (0.98 g, 95%). This enamine was used directly in the next step.
[0137] A mixture of the enamine (1.0 g, 2.71 mmol) and sulfur (1.1 9, 34.31 mmol) in decalin
(10 mL) was lowered into an oil bath preheated to 170°C. The mixture was stirred 20
minutes; then it was cooled and the decalin was removed by short path distillation.
The residue was dissolved in carbon disulfide and flash chromatographed on silica
gel (1 x 6 inches). Elution with carbon disulfide removed residual sulfur. Continued
elution with 50% ethyl acetate/hexane and finally with pure ethyl acetate gave 0.09
g of brown oil. The product was combined with 0.03 g of product from a previous preparation
and treated with decolorizing carbon in ether. Recrystallization from hexane gave
0.026 g (2.6%) of the title product as a light yellow solid: mp 67.5-68°C. Analysis
calculated for C
22H
23ClN
2O: C, 72.02; H, 6.32; N, 7.64. Found: C, 71.95; H, 6.32; N, 7.47.
Example 55
7-Trifluoromethylsulfonyloxy-1-(4-methyl-1-piperazinyl)-naphthalene
[0138] 7-Hydroxy-1-(4-methyl-1-piperazinyl)-naphthalene (4.1 g, 16.9 mmol) and triethylamine
(12.8 mL, 91.8 mmol) were dissolved in methylene chloride (150 mL) and cooled to -78°C.
Triflic anhydride (3.04 mL, 18.1 mmol) was added via syringe and the reaction was
warmed to room temperature and stirred overnight. The reaction was again chilled to
-78°C and additional triflic anhydride (1 mL) and triethylamine (2 mL) were added
but after 2 hours stirring at ambient temperature, no further reaction occurred. Saturated
ammonium chloride was added and the mixture was concentrated. The residue was partitioned
between ethyl acetate and water. The organic layer was washed with water and brine,
dried over magnesium sulfate and concentrated to a brown oil which was purified by
silica gel flash chromatography (2 x 6 inches). Elution with 75% ethyl acetate/hexane
gave 4.49 g (71%) of the title product as a light brown solid: mp 70-71°C. Analysis
calculated for C
16H
17F
3N
2O
3S: C, 51.33; H, 4.58; N, 7.48. Found: C, 51.35; H, 4.46; N, 7.49.
Example 56
7-Benzamido-1-(4-methyl-1-piperazinyl)-naphthalene
[0139] 7-Benzamido-1-(4-methyl-1-piperazinyl)-3,4-dihydronaphthalene (0.795 g, 2.29 mmol,
an intermediate from Example 1), freshly distilled dicyclopentadiene (70°C at 1 Torr,
0.909 g, 6.87 mmol), and 10% palladium on carbon (0.2 g, predried) were combined in
xylene (25 mL) and refluxed 4 hours. The mixture was cooled and additional palladium
on carbon (0.3 g) was added. The reaction was refluxed vigorously and xylene was distilled
out of the reaction until the volume of the reaction was reduced to about 10 mL. The
reaction was refluxed overnight, cooled, and filtered through celite. The filtrate
was concentrated on silica gel and flash chromatographed on silica gel. Gradient elution
with from 50% to 100% ethyl acetate/hexane gave a forerun containing an unweighed
amount of 7-benzamido-α-tetralone. Continued gradient elution with 2% to 10% methanol/ethyl
acetate gave 0.49 g (62%) of the title product: mp 172-173.5°C.
[0140] Alternatively, [2,2,2] bicyclooctene was used in place of dicyclopentadiene in the
above dehydrogenation reaction to produce the title product in 66% yield after recrystallization
from ethyl acetate/hexane.
Example 57
7-Amino-1-(1-methyl-4-piperidinyl)-naphthalene
[0141] The following reaction was run in two side by side reactions and the crude products
were combined for work up and purification. A mechanically stirred solution of 8-bromo-2-(dibenzylamino)-naphthalene
(10.0 g, 24.9 mmol from Preparation 4) in tetrahydrofuran (200 mL) was cooled to -95°C
(hexane/liquid nitrogen) and butyllithium (10.39 mL, 24.9 mmol, 2.4 M) was added dropwise.
The orange solution was stirred 7 min, then 1-methyl-4-piperidone (2.82 g, 24.9 mmol)
was added dropwise over 10 minutes with a 10 mL tetrahydrofuran rinse. The orange
color faded while stirring was continued 20 minutes at -100°C. The reaction was allowed
to warm to room temperature and quenched with water. The solvent was removed and the
residue was partitioned between methylene chloride and water (at this point the two
reactions were combined). The phases were separated and the organic layer was washed
with brine, dried, and concentrated onto silica gel. Flash chromatography (4 x 4 inches
silica gel) proceeded as follows: methylene chloride (1 L) and 2% methanol / methylene
chloride (1.6 L) unweighed white solid 7-dibenzylaminonaphthalene; 15% methanol /
methylene chloride (1 L), 25% methanol / methylene chloride (1 L) and 30% methanol
/ methylene chloride / 0.2% ammonium hydroxide (4 L) product contaminated with water.
The combined eluents were concentrated and redissolved in methylene chloride. The
solution was dried and concentrated to afford 15.09 g (69%) of 7-dibenzylamino-1-(4-hydroxy-1-methyl-4-piperidinyl)-naphthalene
as a light tan foam. A sample recrystallized from ethyl acetate had mp 173-174°C.
Analysis calculated for C
30H
32N
2O: C, 82.53; H, 7.39; N, 6.42. Found: C, 82.42; H, 7.44; N, 6.38.
[0142] The product from the above reaction (15.0 g, 34.38 mmol), p-toluenesulfonic acid
(7.85 g, 41.26 mmol) and toluene (500 mL) were combined and refluxed 4 hours with
azeotropic removal of water. The mixture was allowed to stand at room temperature
48 hours, then additional p-toluenesulfonic acid (1.4 g) was added and the mixture
was refluxed 5 hours more. The reaction was concentrated at reduced pressure and the
residue was taken up in methylene chloride. This organic phase was washed with 1 N
sodium hydroxide (2 x) and brine, then it was dried over calcium sulfate and concentrated
to give 7-dibenzylamino-1-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-naphthalene as a
brown oil which crystallized on standing (13.8 g, 96%). This material was suitable
for use in the next reaction. A sample recrystallized from ethyl acetate had mp 124-126°C.
The analytical sample was recrystallized from isopropanol. Analysis calculated for
C
30H
30N
2 · 0.5 H
2O: C, 84.27; H, 7.31; N, 6.69. Found: C, 83.85; H, 6.97; N, 6.39.
[0143] A mixture of 7-dibenzylamino-1-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-naphtha lene
(2.85 g, 6.81 mmol) and palladium hydroxide (20% on carbon, 2.06 g) in glacial acetic
acid (60 mL) was hydrogenated 22 hours (starting pressure approximately 50 psi). Additional
palladium hydroxide (1 g) was added and hydrogenation was continued 13 hours more.
The reaction was filtered through celite. The filtrate was neutralized with 4 N sodium
hydroxide and extracted with methylene chloride. This organic phase was washed with
brine, dried and concentrated to 1.3 g of brown oil. Crystallization from isopropanol
gave 0.544 g (33%) of 7-amino-1-(1-methyl-4-piperidinyl)-naphthalene as light brown
crystals. mp 169.5-171 °C. Analysis calculated for C
16H
20N
2: C, 79.96; H, 8.39; N, 11.66. Found: C, 80.14; H, 8.42; N, 11.52.
Example 58
7-(3-nitro-2-pyridylamino)-1-(1-methyl-4-piperidinyl)-naphthalene
[0144] A mixture of the product from Example 57 (0.338 g, 1.4 mmol), 2-chloro-3-nitropyridine
(0.446 g, 2.81 mmol), and 4-dimethylaminopyridine (0.172 g, 1.4 mmol) in dimethylformamide
(6 mL) was refluxed 5 hours. The solvent was removed at reduced pressure and the residue
was taken up in methylene chloride. The organic phase was washed with 1 N sodium hydroxide
and brine, then it was concentrated onto silica gel and flash chromatographed (1 x
4 inches silica gel). The elution proceeded as follows: 75% methylene chloride / hexane
(175 mL) nil; methylene chloride (250 mL) unweighed excess 2-chloro-3-nitropyridine;
2% methanol / methylene chloride (200 mL) nil, (550 mL) 0.373 g of crude product contaminated
with 4-dimethylamino-pyridine. This material was triturated with ether and filtered
to give 0.17 g of title product as orange crystals.
1H NMR δ 10.34 (br s, 1 H), 8.59 (dd, J = 2, 8.5 Hz, 1 H), 8.54-8.50 (m, 2 H), 7.88
(d, J = 9 Hz, 1 H), 7.72-7.70 (m, 1 H), 7.66 (dd, J = 2, 9 Hz, 1 H), 7.45-7.41 (m,
2 H), 6.89 (dd, J = 4.5, 8.5 Hz, 1 H), 3.27 (tt, J = 4, 11.5 Hz, 1 H), 3.11 (long
range coupled d, J = 11.5 Hz, 1 H), 2.41 (s, 3 H), 2.27 (dt, J = 2.5, 11.5 Hz, 2 H),
2.09-1.89 (m, 4 H).
Example 59
7-(Imidazolo[4,5-b]pyridin-1-yl)-1-(1-methyl-4-piperidinyl)-naphthalene
[0145] A mixture of the product from Example 58 (0.18 g, 0.5 mmol) and 10% palladium on
carbon (0.04 g) in ethanol (35 mL) and ethyl acetate (15 mL) was hydrogenated at 45
psi for 4 hours. The mixture was filtered through celite and concentrated to give
7-(3-amino-2-pyridylamino)-1-(1-methyt-4-piperidinyl)-naphthalene which was suitable
for further reaction;
1H NMR δ 8.07 (d, J = 2 Hz, 1 H), 7.89 (dd, J = 1.5, 5 Hz, 1 H), 7.79 (d, J = 9 Hz,
1 H), 7.64 (d, J = 7.5 Hz, 1 H), 7.45 (dd, J = 2, 9 Hz, 1 H), 7.36-7.26 (m, 2 H with
CHCl
3 from NMR solvent overlapping), 7.07 (dd; J = 1.5, 7.5 Hz, 1 H), 6.82 (dd, J = 5,
7.5 Hz, 1 H), 6.51 (br s, 1 H), 3.49 (br s, 2 H), 3.18 (tt, J = 4, 12 Hz, 1 H), 3.03
(long range coupled d, J = 13.5 Hz, 2 H), 2.39 (s, 3 H), 2.23 (dt, J = 2.5, 11.5 Hz,
2 H), 2.08-1.87 (m, 4 H). HRMS m/e calculated for C
21H
24N
4: 332.1996. Observed m/e 332.2003.
[0146] The product from the above reaction and ethoxymethylenemalononitrile (0.079 g, 0.646
mmol) were combined in glacial acetic acid (7 mL) were refluxed 4 hours. The solvent
was removed at reduced pressure and the residue was taken up in methylene chloride.
The organic phase was washed with 1 N sodium hydroxide and brine, then it was dried
and concentrated. This residue was flash chromatographed on silica gel (1 x 3.5 inches).
Gradient elution with from 50% ethyl acetate / hexane to pure ethyl acetate and then
with from 2% to 5% methanol / ethyl acetate gave no product. Continued elution with
from 15% to 40% methanol / ethyl acetate gave a tan foam product. Treatment with charcoal
in methylene chloride, filtration and concentration gave 0.155 g of product. Recrystallization
from ethyl acetate gave 0.04 g (23%) of the title compound as off white crystals.
mp 118-120°C. Analysis calculated for C
22H
22N
4: C, 77.16; H, 6.48; N, 16.36. Found: C, 76.99, H, 6.45; N, 16.27.
Example 60
7-(4-Chlorobenzamido-1-(1-methyl-4-piperidinyl)-naphthalene
[0147] The product from Example 57 (0.202 g, 0.845 mmol), triethylamine (0.124 mL, 0.93
mmol) and 4-chlorobenzoyl chloride (0.118 mL, 0.93 mmol) were combined in acetonitrile
(10 mL) at 0°C. The mixture was allowed to come to room temperature and stir overnight.
The reaction was chilled back to 0°C and a second equivalent of acid chloride and
triethylamine were added. The mixture was heated to 90°C overnight. The solvent was
removed at reduced pressure and the residue was taken up in methylene chloride. The
organic phase was washed with brine, dried, concentrated onto silica gel and flash
chromatographed (0.5 x 3.5 inches). Elution proceeded as follows: methylene chloride
then gradient elution with from 2% to 4% methanol / methylene chloride was unproductive.
Continued elution with from 4% to 6% methanol / methylene chloride gave 0.214 g of
white foam. Recrystallization from chloroform / ether gave 0.115 g of the title compound
as tan crystals. mp 162-164°C. The compound was converted to its hydrochloride salt
with HCI in ether. Analysis calculated for C
23H
23ClN
2O · HCl: C, 66.51; H, 5.82; N, 6.74. Found: C, 66.12; H, 5.76; N, 6.41.
Example 61
7-Amino-1-(1-methyl-3-piperidinyl)-naphthalene
[0148] A solution of 8-bromo-2-(dibenzylamino)-naphthalene (9.75 g, 24.3 mmol product of
Preparation 4) in tetrahydrofuran (270 mL) was cooled to -78°C and butyllithium (9.72
mL, 24.4 mmol, 2.4 M) was added dropwise. The orange solution was stirred 20 minutes,
then 1-t-butoxycarbonyl-3-piperidone (4.84 g, 24.3 mmol dissolved in 5 mL tetrahydrofuran
) was added dropwise with a 5 mL tetrahydrofuran rinse. The reaction was stirred 30
minutes at -78°C, then allowed to warm to room temperature and stir 1 hour. The solvent
was removed and the residue was partitioned between methylene chloride and water.
The phases were separated and the organic layer was washed with brine, dried over
calcium sulfate, and concentrated onto silica gel. Flash chromatography (3 x 3 inches
silica gel) proceeded as follows: 5% ethyl acetate / hexane (1.4 L) and 10% ethyl
acetate / hexane (1 L) unweighed white solid 7-dibenzylaminonaphthalene; 25%ethyl
acetate / hexane (1.5 L) 6.46 g (51%) of 7-dibenzylamino-1-(1-t-butoxycarbonyl-3-hydroxy-3-piperidinyl)-na
phthalene which was suitable for use without further purification. A sample recrystallized
from ethyl acetate / hexane had mp 145-147°C.
[0149] The product of the above reaction (1.0 g, 1.9 mmol) and dry benzene (20 mL) were
chilled to 0°C and Burgess salt (0.958 g, 4.02 mmol) was added. The mixture was heated
to 55°C for 2 hours, then allowed to stir at ambient temperature overnight. Water
was added and after stirring an additional 15 minutes, the phases were separated.
The organic layer was washed with brine and the combined aqueous washes were back
extracted with ethyl acetate. The combined organic layer was dried over calcium sulfate,
concentrated onto silica gel and flash chromatographed (1 x 3 inches). Elution 2%
to 4% ethyl acetate / hexane gave 0.68 g (70%) of a mixture of both possible dehydration
products (7-dibenzylamino-1-(1-t-butoxycarbonyl-1,4,5,6-tetrahydropyrid-3-yl)-naphthalene
and 7-dibenzylamino-1-(1-t-butoxycarbonyl-1,2,5,6-tetrahydropyrid-3-yl)-naphthalene).
The products could be separated by careful chromatography but were carried as a mixture
in this sequence.
[0150] A slurry of lithium aluminum hydride (0.172 g, 4.52 mmol) in tetrahydrofuran (20
mL) was chilled to 0°C and the product of the above reaction (0.568 g, 1.13 mmol in
5 mL tetrahydrofuran) was added with a tetrahydrofuran rinse (2 x 2.5 mL). The mixture
was refluxed 4 hours, chilled to 0°C and quenched with sodium sulfate decahydrate.
The reaction was filtered and the filter cake was rinsed well with methylene chloride.
The filtrate was concentrated and the residue was taken up in methylene chloride.
This organic phase was washed with water and brine, dried and concentrated to give
0.455 g of a 2:1 mixture of olefin products (7-dibenzylamino-1-(1-methyl-1,4,5,6-tetrahydropyrid-3-yl)-naphthalene
and 7-dibenzylamino-1-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)naphthalene) as judged
by integration of the methyl signals in the NMR spectrum (2.52 ppm - major and 2.27
ppm - minor). This material was carried on without further purification or characterization.
[0151] The product mixture from the above reaction (4.0 g, 9.56 mmol) and palladium hydroxide
(20% on carbon, 3.75 g) in glacial acetic acid (141 mL) and ethanol (141 mL) was hydrogenated
4 hours (starting pressure approximately 50 psi). Additional palladium hydroxide (0.8
g) was added and hydrogenation was continued 5 hours more. The reaction was filtered
through celite. The filtrate was neutralized with 4 N sodium hydroxide and extracted
with methylene chloride. This organic phase was washed with brine, dried, concentrated
onto silica gel and flash chromatographed (2 x 3 inches). Elution proceeded as follows:
75% ethyl acetate / hexane (400 mL), ethyl acetate (400 mL), and 2% methanol / ethyl
acetate (400 mL), nil; 2% triethylamine / 5% methanol / ethyl acetate (400 mL), 0.45
g of an unidentified brown foam; 2% triethylamine / 6% methanol / ethyl acetate (500
mL) and 3% triethylamine / 8% methanol / ethyl acetate (500 mL), 1.35 g (54%) of brown
foam title product. Further purification by treatment with activated charcoal followed
by trituration in ether gave 0.362 g of the title compound as pink crystals which
had mp 117-120°C. HRMS m/e calculated for C
16H
20N
2: 240.1622. Observed m/e 240.1623. Analysis calculated for C
16H
20N
2: C, 79.96; H, 8.39; N, 11.66. Found: C, 80.02; H, 8.22; N, 11.10.
Example 62
7-(3-Nitro-2-pyridylamino)-1-(1-methyl-3-piperidinyl)-naphthalene
[0152] A mixture of 7-amino-1-(1-methyl-3-piperidinyl)-naphthalene (0.252 g, 1.05 mmol from
Example 61), 2-chloro-3-nitropyridine (0.333 g, 2.1 mmol) and collidine (0.139 mL,
1.05 mmol) in dimethylformamide (10 mL) was refluxed overnight. The reaction was concentrated
at reduced pressure and the residue was taken up in methylene chloride. The organic
phase was washed with 0.5 N sodium hydroxide and brine, dried, concentrated onto silica
gel and flash chromatographed (1 x 3 inches). Elution proceeded as follows: 50% ethyl
acetate / hexane (500 mL) unweighed forrun; 75% ethyl acetate / hexane (400 mL) and
ethyl acetate (100 mL) 0.151 g (51%) of red oil product. A sample crystallized from
ether gave the title compound as red crystals. mp 107-108°C. Analysis calculated for
C
21H
22N
4O
2: C, 69.59; H, 6.12; N, 15.46. Found: C, 69.30; H, 5.91; N, 14.92.
Example 63
7-(Imidazolo[4,5-b]pyridin-1-yl)-1-(1-methyl-3-piperidinyl)-naphthalene
[0153] A mixture of the 7-(3-nitro-2-pyridylamino)-1-(1-methyl-3-piperidinyl)-naphthalene
(0.12 g, 0.33 mmol from Example 62) and 10% palladium on carbon (0.03 g) in ethanol
(10 mL) and methanol (20 mL) was hydrogenated at 50 psi for 4 hours. The reaction
was filtered through celite and concentrated to the brown oil product (7-(3-amino-2-pyridylamino)-1-(1-methyl-3-piperidinyl)-naphthalene)
which was suitable for use without further purification.
1H NMR δ 7.89-7.83 (m, 2 H), 7.78 (d, J = 9 Hz, 1 H), 7.64 (dd, J = 2, 9 Hz, 2 H),
7.33-7.23 (m, 2 H, partially obscurred by NMR solvent), 7.02 (dd, J = 1.5, 7.5 Hz,
1 H), 6.78 (dd, J = 5, 7.5 Hz, 1 H), 6.55 (br s, 1 H), 3.54 (long range coupled t,
J = 11.5 Hz, 1 H), 3.18 (long range coupled dd, J = 1.5, 11 Hz, 1 H), 2.99 (long range
coupled d, J = 10.5 Hz, 1 H), 2.34 (s, 3 H), 2.17-1.97 (m, 3 H), 1.94-1.81 (sym m,
2 H), 1.69-1.51 (m, 1H). HRMS m/e calculated for C
21H
24N
4: m/e 332.2000. Observed m/e 332.2002.
[0154] A mixture of 7-(3-amino-2-pyridylamino)-1-(1-methyl-3-piperidinyl)-naphthalene (0.104
g, 0.313 mmol) and ethoxymethylenemalononitrile (0.056 g, 0.459 mmol) in glacial acetic
acid (5 mL) was refluxed 6 hours. The reaction was cooled, neutralized with 4 N sodium
hydroxide and extracted with methylene chloride. The organic phase was washed with
brine, dried over calcium sulfate, concentrated onto silica gel and flash chromatographed
(1 x 2 inches). Elution proceeded as follows: 50% ethyl acetate / hexane (200 mL),
75% ethyl acetate / hexane (200 mL), ethyl acetate (200 mL) and 1% methanol / 1% triethylamine
/ ethyl acetate (300 mL) nil; 3% methanol / 3% triethylamine / ethyl acetate (300
mL) 0.075 g (70 %) of 7-(Imidazolo[4,5-b]pyridin-1-yl)-1-(1-methyl-3-piperidinyl)-naphthalene
as a faint green oil. The product was characterized as its HCI salt which crystallized
from isopropanol. mp > 250°C.
1H NMR (D
2O) δ 9.30 (br s, 1 H), 8.51 (d, J = 5 Hz, 1 H), 8.40 (s, 1 H), 8.32 (d, J = 7.5 Hz,
1 H), 8.11 (d, J = 9 Hz, 1 H), 7.94 (d, J = 8 Hz, 1 H), 7.73 (dd, J = 2, 9 Hz, 1 H),
7.68-7.53 (m, 3 H), 3.77 (long range coupled t, J = 11.5 Hz, 1 H), 3.62 (br t, J =
10.5 Hz, 2 H), 3.22 (t, J = 12.5 Hz, 1 H), 3.07 (sym m, 1 H), 2.87 (s, 3 H), 2.23-2.05
(m, 2 H), 2.04-1.78 (sym m, 2 H). Analysis calculated for C
22H
22N
4 · 2HCl · H
2O: C, 60.97; H, 6.05; N, 12.93. Found: C, 60.89; H, 6.00; N, 12.61.
Example 64
7-Benzamido-1-(1-methyl-3-piperidinyl)-naphthalene
[0155] A mixture of 7-amino-1-(1-methyl-3-piperidinyl)-naphthalene (0.203 g, 0.845 mmol,
product of example 61) and triethylamine (0.141 mL, 1.01 mmol) in tetrahydrofuran
(5 mL) was chilled to 0°C and benzoyl chloride (0.118 mL, 1.01 mmol) was added. The
mixture was warmed to room temperature and stirred overnight. The reaction was concentrated
at reduced pressure and the residue was taken up in methylene chloride. The organic
phase was extracted with 0.5 N sodium hydroxide and brine, dried, concentrated onto
silica gel and flash chromatographed (1 x 2 inches). Elution proceeded as follows:
50% ethyl acetate / hexane (225 mL), 75% ethyl acetate / hexane (150 mL) nil; 75%
ethyl acetate / hexane (400 mL) and ethyl acetate (200 mL) 0.198 g of pink foam. This
product was converted to an HCI salt in methanol, treated with activated carbon, and
filtered. The filtrate was concentrated and triturated with ether to give 0.091 g
(31%) of the title compound as an amorphous solid with a melting range of 140-170°C.
1H NMR (DMSO
d6)
δ 10.59 (s, 1 H), 10.34 (br s, 1 H), 8.73 (s, 1 H), 8.06 (d, J = 7 Hz, 2 H), 7.94 (distorted
t, J = 10 Hz, 2 H), 7.82 (d, J = 7 Hz, 1 H), 7.63-7.53 (m, 3 H), 7.47-7.39 (m, 2 H),
3.78 (br t, J = 12 Hz, 1 H), 3.56 (br t, J = 11 Hz, 2 H), 3.05 (br s, 1 H), 2.83 (br
s, 3 H), 2.15-1.97 (m, 2 H), 1.71 (br s, 1 H), HRMS m/e calculated for C
23H
24N
2O: m/e 344.1883. Observed m/e 344.1886.
Example 65
7-(4-Chlorobenzamido)-1-(4-methoxyethyl-1-piperazinyl)-naphthalene
[0156] A mixture of 7-(4-chlorobenzamido)-1-(1-piperazinyl)-naphthalene (0.15 g, 0.41 mmol,
product of example 12), sodium iodide (0.064 g, 0.431 mmol), triethylamine (0.164
mL, 0.431 mmol) and 2-bromoethyl methyl ether (0.040 mL, 0.431 mmol) in acetonitrile
(7 mL) was refluxed overnight. The reaction was cooled and concentrated at reduced
pressure. The residue was taken up in methylene chloride and washed with 1 N sodium
hydroxide and brine, dried, concentrated onto silica gel and flash chromatographed
(1 x 2.5 inches). Elution proceeded as follows: 50% ethyl acetate / hexane (100 mL)
and 75% ethyl acetate / hexane (100 mL), nil; 75% ethyl acetate / hexane (100 mL)
and ethyl acetate (150 mL), 0.121 g (69%) of 7-(4-chlorobenzamido)-1-(4-methoxyethyl-1-piperazinyl)-naphthalene
as an oil. This oil was converted to the HCI salt from an ether solution. An amorphous
white powder hydrochloride salt of the title compound was obtained. mp 134-148°C.
1H NMR δ 8.54 (br s, 1 H), 8.05 (br s, 1 H), 7.84 (long range coupled t, J = 9 Hz,
3 H), 7.66 (dd, J = 2, 9 Hz, 1 H), 7.55-7.43 (m, 3 H), 7.36 (t, J = 8 Hz, 1 H), 7.11
(dd, J = 1, 7.5 Hz, 1 H), 3.57 (t, J = 5.5 Hz, 2 H), 3.38 (s, 3 H), 3.19 (br s, 4
H), 2.83 (br s, 4 H), 2.70 (t, J = 5.5 Hz, 2 H). Analysis calculated for C
24H
26ClN
3O
2•2HCl•1.5H
2O: C, 55.02; H, 5.96; N, 8.02. Found: C, 55.53; H, 6.31; N, 7.78.
Example 66
7-(4-Chlorobenzamido)-1-(4-propyl-1-piperazinyl)-naphthalene
[0157] A mixture of 7-(4-chlorobenzamido)-1-(1-piperazinyl)-naphthalene (0.20 g, 0.547 mmol,
the product of Example 12), propionaldehyde (0.041 mL, 0.563 mmol) and sodium cyanoborohydride
(0.103 g, 1.64 mmol) in methanol (12 mL) and acetic acid (1.2 mL) was stirred at ambient
temperature for 20 hours. The solvent was removed at reduced pressure and the residue
was partitioned between methylene chloride and saturated aqueous sodium bicarbonate.
Phases were separated and the organic layer was washed with brine, dried, concentrated
onto silica gel and flash chromatographed (1 x 3 inches). Elution proceeded as follows:
ethyl acetate (50 mL) unweighed forrun; ethyl acetate (250 mL) 0.164 g of yellow foam.
The foam was triturated with pentane and 0.079 g (28%) of the title compound was collected
as a white solid. mp 130-132°C. Analysis calculated for C
24H
26ClN
3O: C, 70.66; H, 6.42; N, 10.30. Found: C, 70.91; H, 6.66; N, 10.50.
Example 67
7-(4-Chlorobenzamido)-1-(4-ethyl-1-piperazinyl)-naphthalene
[0158] A solution of 7-(4-chlorobenzamido)-1-(1-piperazinyl)-naphthalene (0.197 g, 5.39
mmol, the product of Example 12) in tetrahydrofuran (14 mL) was chilled to -78°C and
butyllithium (0.454 mL, 1.13 mmol, 2.5 M) was added in three portions. The yellow
solution was stirred 5 minutes, then ethyl iodide (0.045 mL, 0.566 mmol) was added
and the reaction was allowed to warm to room temperature. The mixture was treated
with saturated aqueous ammonium chloride and the solvent was removed at reduced pressure.
The residue was taken up in methylene chloride and extracted with saturated aqueous
sodium bicarbonate and brine, dried, concentrated onto silica gel and flash chromatographed
(1 x 2.5 inches). Elution proceeded as follows: 75% ethyl acetate / hexane (150 mL),
nil; 90% ethyl acetate / hexane (200 mL) and ethyl acetate (200 mL), 0.135 g of a
light yellow foam. This foam was triturated with pentane and 0.112 g (52%) of the
title compound was collected as a white powder. mp 173-174.5°C. Analysis calculated
for C
23H
24ClN
3O: C, 70.13; H, 6.14; N, 10.67. Found: C, 70.21; H, 6.32; N, 10.79.
Example 68
7-Amino-1-(1-methyl-3-pyrrolidinyl)-naphthalene
[0159] A solution of 8-bromo-2-(dibenzylamino)-naphthalene (2.035 g, 5.07 mmol, preparation
4) in tetrahydrofuran (50 mL) was chilled to -78°C and butyllithium (2.03 mL, 5.07
mmol, 2.5 M) was added dropwise. The dark solution was stirred 10 minutes, then 1-t-butoxycarbonyl-3-pyrrolidinone
(0.939 g, 5.07 mmol in 4 mL tetrahydrofuran) was added dropwise with a 4 mL tetrahydrofuran
rinse. The reaction was allowed to warm to room temperature and the solvent was removed.
The residue was taken up in methylene chloride and washed with water, saturated aqueous
ammonium chloride, saturated aqueous sodium bicarbonate, and brine. The organic phase
was dried over calcium sulfate, concentrated onto silica gel and flash chromatographed
(1.5 x 3 inches). Elution proceeded as follows: 5% ethyl acetate / hexane (700 mL),
unweighed forrun; 10% ethyl acetate / hexane (200 mL), nil; 25% ethyl acetate / hexane
(300 mL), 0.94 g of 7-dibenzylamino-1-(1-t-butoxycarbonyl-3-hydroxy-3-pyrrolidinyl)-naphthalene
as a yellow oil which was suitable for use without further purification. A sample
crystallized from ethyl acetate had mp 114-117°C.
1H NMR δ 7.69 (d, J = 9 Hz, 1 H), 7.63 (d, J = 8 Hz, 1 H), 7.51 (d, J = 2 Hz, 1 H),
7.42-7.33 (m, 8 H), 7.32-7.22 (m, 3 H, partially obscurred by NMR solvent), 7.21-7.06
(m, 2 H), 4.81 (t, J = 21 Hz, 4 H), 3.99 (sym m, 1 H), 3.75 (sym m, 1 H), 3.58-3.35
(m, 1 H), 3.34-3.17 (m, 1 H), 2.29-2.10 (m, 1 H), 2.02-1.88 (m, 1 H), 1.90 (s, 1 H),
1.49 (s, 9 H).
[0160] A solution of 7-dibenzylamino-1-(1-t-butoxycarbonyl-3-hydroxy-3-pyrrolidinyl)naphthalene
(1.0 g, 1.97 mmol) in benzene (20 mL) was chilled on wet ice (precipitate) and Burgess
salt (0.89 g, 3.74 mol) was added all at once. The mixture was heated to 55°C for
2 hours. The reaction was cooled and extracted with water and brine. The combined
aqueous phase was back extracted with ethyl acetate and the combined organic layer
was dried over calcium sulfate. The organic layer was concentrated onto silica gel
and flash chromatographed (1 x 2.5 inches). Elution with 5% ethyl acetate / hexane
(1300 mL) gave 0.764 g (79%) of a brown solid which was a mixture of two dehydration
products which were used directly in the next reaction.
[0161] A slurry of lithium aluminum hydride (1.78 g, 46.92 mmol) in tetrahydrofuran (220
mL) was chilled to 0°C and the product of the above reaction (5.75 g, 11.73 mmol)
was added in tetrahydrofuran (10 mL with 2 x 10 mL rinses). The mixture was refluxed
5 hours, chilled to 0°C and carefully quenched with sodium sulfate decahydrate. The
reaction was filtered and the filter cake was rinsed well with methylene chloride.
The filtrate was concentrated at reduced pressure and the residue was taken up in
methylene chloride. The organic phase was washed with brine, dried, and concentrated
to give 4.58 g of a brown oil which was a 2:1 mixture of olefinic products as judged
by integration of the methyl singlet at 2.48 ppm (major) and 2.31 ppm (minor) from
the NMR spectrum. The mixture was used directly in the next step.
[0162] A mixture of the product of the above reaction (4.58 g) and 20% palladium hydroxide
on carbon (4.7 g) in ethanol (161 mL) and acetic acid (161 mL) was hydrogenated at
about 50 psi for 5.5 hours. The reaction was filtered through celite and the filtrate
was concentrated at reduced pressure. The residue was neutralized with 4 N sodium
hydroxide and extracted with methylene chloride. The organic phase was washed with
brine, dried over calcium sulfate, concentrated onto silica gel and flash chromatographed
(2 x 3.25 inches). Elution proceeded as follows: ethyl acetate (200 mL), nil; 1% triethylamine
/ 1% methanol / ethyl acetate (500 mL) and 2% triethylamine / 2% methanol / ethyl
acetate (500 mL), nil; 5% triethylamine / 5% methanol / ethyl acetate (500 mL) and
10% triethylamine / 10% methanol / ethyl acetate (400 mL), 0.90 g of the title compound
as a brown oil.
1H NMR δ 7.66 (d, J = 8.5 Hz, 1 H), 7.56 (d, J = 8 Hz, 1 H), 7.41 (d, J = 7 Hz, 1 H),
7.24 (s, 1 H, partially obscurred by NMR solvent), 7.19 (t, J = 7.5 Hz, 1 H), 6.94
(dd, J = 2.5, 8.5 Hz, 1 H), 4.20-3.96 (m, 1 H), 3.87 (br s, 2 H), 3.08 (t, J = 8.5
Hz, 1 H), 2.91-2.70 (m, 3 H), 2.45 (s, 3 H). This material was suitable for use without
further purification.
Example 69
7-Benzamido-1-(1-methyl-3-pyrrolidinyl)-naphthalene
[0163] A solution of 7-amino-1-(1-methyl-3-pyrrolidinyl)-naphthalene (0.139 g, 0.615 mmol,
product of Example 68) and triethylamine (0.103 mL, 0.738 mmol) In tetrahydrofuran
(5 mL) was chilled to 0°C and benzoyl chloride (0.086 mL, 0.738 mmol) was added. The
reaction was warmed to room temperature and stirred overnight. The solvent was removed
at reduced pressure and the residue was taken up in methylene chloride. The organic
layer was washed with 0.5 N, sodium hydroxide and brine, dried, concentrated onto
silica gel and flash chromatographed (1 x 2 inches). Elution proceeded as follows:
50% to 75% ethyl acetate / hexane (375 mL), nil; ethyl acetate (200 mL), nil; 2% triethylamine
/ 2% methanol / ethyl acetate (200 mL), 0.14 g of brown oil which partially crystallized.
Recrystallization from ethyl acetate gave 0.058 g, (28%) of the title compound as
white crystals. mp 137-145°C;
1H NMR δ 8.57 (d, J = 2 Hz, 1 H), 8.06 (br s, 1 H), 7.95 (dd, J = 1.5, 8 Hz, 2 H),
7.86 (d, J = 9 Hz, 1 H), 7.71-7.64 (m, 2 H), 7.59-7.49 (m, 4 H), 7.40 (t, J = 7.5
Hz, 1 H), 4.15 (sym m, 1 H), 3.04 (t, J = 9 Hz, 1 H), 2.93-2.81 (m, 2 H), 2.80-2.68
(m, 1 H), 2.66-2.50 (m, 1 H), 2.47 (s, 3 H), 2.08-1.96 (m, 1 H). Analysis calculated
for C
22H
22N
2O: C, 79.97; H, 6.71; N, 8.48. Found: C, 79.36; H, 6.72; N, 7.94.
Example 70
7-Amino-1-(1-t-butoxycarbonyl-pyrrolidin-2-(R)-ylmethyl)-naphthalene
[0164] A solution of 8-bromo-2-(dibenzylamino)-naphthalene (5.0 g, 12.0 mmol, preparation
4) in tetrahydrofuran (300 mL) was chilled to -78°C and butyllithium (5.0 mL, 12.5
mmol, 2.5 M) was added dropwise to generate a dark red solution. A tetrahydrofuran
solution (40 mL) of 1-t-butoxycarbonyl-R-prolinal (2.61 g, 13 mmol) was added dropwise
with a 10 mL tetrahydrofuran rinse. The reaction was stirred an additional 10 minutes,
then carbon disulfide (0.95 mL, 16 mmol, predried over calcium sulfate) was added.
The reaction color changed from green to brown and finally to orange. After stirring
30 minutes at -78°C, methyl iodide (0.82 mL, 13 mmol) was added and the reaction was
allowed to warm to ambient temperature and stir 2 hours. Aqueous ammonium chloride
and ether were added and the phases were separated. The organic layer was washed with
water and brine, dried over magnesium sulfate, concentrated onto silica gel and flash
chromatographed (2 x 6 inches). Elution proceeded as follows: 2% ether / hexane (1
L), unweighed impurity; 5% ether / hexane (1000 mL), 10% ether / hexane (1000 mL),
and 20% ether / hexane (1000 mL), 5.74 g (78%) of the xanthate intermediate as a mixture
of diastereomers which was used directly in the next step.
[0165] A solution of the xanthate from the above reaction (5.74 g, 9.37 mmol) in toluene
(300 mL) was heated to reflux and AIBN (0.26 g) (AIBN=azo(bis) isobutyronitrile) and
tributyltin hydride (11.7 mL, 43.5 mmol) were added in three portions first at initial
reflux and then after 1 and 2 hours of reflux. The reaction was refluxed an additional
1.5 hours, cooled to room temperature and allowed to stir overnight. The reaction
was concentrated onto silica gel and flash chromatographed (2 x 8 inches). Elution
proceeded as follows: hexane (1000 mL), unweighed tin impurities; 2% ether / hexane
(2 L) and 3% ether / hexane (2 L), unweighed impurities; 5% ether / hexane (3 L),
3.07 g (65%) of 7-dibenzylamino-1-(1-t-butoxycarbonylpyrrolidin-2-(R)-ylmethyl)- naphthalene
as a hard yellow-green foam.
[0166] A mixture of 7-dibenzylamino-1-(1-t-butoxycarbonyl-pyrrolidin-2-(R)-ylmethyl)naphthalene
(0.68 g, 1.34 mmol) and 20% palladium hydroxide on carbon (0.25 g) in ethanol (20
mL) and acetic acid (20 mL) was hydrogenated at 50 psi for 8 hours. Additional 20%
palladium hydroxide on carbon (0.25 g) was added and hydrogenation was continued overnight.
The catalyst (0.3 g) was added a third time and hydrogenation was continued 24 hours
more. The reaction was filtered through celite and the pad was washed with ethanol.
The filtrate was concentrated and the residue was taken up in ether. This organic
phase was extracted with saturated aqueous sodium bicarbonate, water and brine, then
it was dried and concentrated to give 0.368 g (84%) of the title compound as a tan
foam. A sample recrystallized from ether / hexane as a light tan solid had mp 157-158.5°C.
Analysis calculated for C
20H
26N
2O
2: C, 73.59; H, 8.03; N, 8.58. Found: C, 73.47; H, 7.93; N, 8.37.
[0167] The S enantiomer of the title compound of Example 70 was prepared using the same
procedure set forth in Example 70, except that 1-t-butoxycarbonyl-(S)-prolinal was
used in place of 1-t-butoxycarbonyl-(R)-prolinal.
Example 71
7-(4-Chlorobenzamido)-1-(pyrrolidin-2-(R)-ylmethyl)-naphthalene
[0168] A solution of 7-amino-1-(1-t-butoxycarbonyl-pyrrolidin-2-(R)-ylmethyl)-naphthal ene
(0.10 g, 0.306 mmol, product of Example 70) and triethylamine (0.085 mL, 6.1 mmol)
in tetrahydrofuran (5 mL) was chilled to 0°C and 4-chlorobenzoyl chloride (0.043 mL,
0.338 mmol) was added. The mixture was allowed to warm to room temperature and stir
2 hours. Ether was added and the reaction was extracted with saturated aqueous sodium
bicarbonate, water, and brine. The organic phase was concentrated onto silica gel
and flash chromatographed (1 x 6 inches). Elution proceeded as follows: 20% ether
/ hexane, unweighed forrun; 30% ether / hexane (200 mL) 0.096 g (68%) of 7-(4-chlorobenzamido)-1-(1-t-butoxycarbonyl-pyrrolidin-2-(R)-ylmethyl)-naphthalene
as a white powder. A sample recrystallized from ether / hexane had mp 136.5-137°C;
[
α]
D = -75.4°, c = 0.195 (chloroform). Analysis calculated for C
27H
29ClN
2O
3: C, 69.74; H, 6.29; N, 6.02. Found: C, 69.75; H, 6.00; N, 6.00.
[0169] To a solution of 7-(4-chlorobenzamido)-1-(1-t-butoxycarbonyl-pyrrolidin-2-(R)-ylme
thyl)-naphthalene (0.09 g, 0.19 mmol) in ether (10 mL) was added ether saturated with
gaseous hydrogen chloride (27 mL) in portions over several hours. The mixture was
stirred overnight and concentrated. The residue was triturated with ether and 0.063
g (80%) of the title compound was collected as a faint pink solid salt. mp 230-231.5°C;
[
α]
D = -46.8°, c = 0.280 (methanol). Analysis calculated for C
22H
21ClN
2O · HCl · 0.5 H
2O: C, 64.39; H, 5.90; N, 6.83. Found: C, 64.49; H, 5.38; N, 6.70.
[0170] The S enantiomer of the title compound of example 71 was prepared using the same
procedure set forth in Example 71, except that 7-amino-1-(1-t-butoxycarbonylpyrrolidin-2-(S)-ylmethyl)-naphthalene
was used in place of 7-(4-chlorobenzamido)-1-(1-t-butoxycarbonyl-pyrrolidin-2-(R)-ylmethyl)-naphthalene.
Example 72
7-Formamido-1-(pyrrolidin-2-(R)-ylmethyl)-naphthalene hydrochloride
[0171] A mixture of 7-amino-1-(1-t-butoxycarbonyl-pyrrolidin-2-(R)-ylmethyl)naphthalene
(0.096 g, 0.294 mmol, product of example 70), triethylamine (0.055 mL, 0.395 mmol)
and acetyl formyl anhydride (0.050 mL, 0.373 mmol) in tetrahydrofuran (5 mL) was refluxed
2 hours. Additional acetyl formyl anhydride (0.020 mL) was added and the reaction
was stirred 1 hour more. The reaction was diluted with ether and extracted with water
and brine. The organic phase was dried, concentrated, and flash chromatographed on
silica gel (1 x 4 Inches). Elution proceeded as follows: 10% ethyl acetate / hexane
(100 mL), nil; 20% ethyl acetate / hexane (350 mL), nil; 25% ethyl acetate / hexane
(750 mL), 0.076 g (73%) of 7-formamido-1-(1-t-butoxycarbonylpyrrolidin-2-(R)-ylmethyl)-naphthalene
as a pale pink oil.
[0172] The oil from the above reaction (0.076 g, 0.214 mmol) was dissolved in ether and
ether saturated with hydrogen chloride (10 mL) was added in 2 mL portions over 1 hour.
The mixture was stirred overnight at ambient temperature. The mixture was concentrated
under a nitrogen stream and the residue was slurried in ether (20 mL). The slurry
was gently refluxed 1 hour and the material was triturated to yield the title compound
as a light tan powder. mp 223.5-224°C; [α]
D = -51.5°, c = 0.295 (methanol). Analysis calculated for C
16H
18N
2O · HCl · 1.5 H
2O: C, 60.47; H, 6.98; N, 8.81. Found: C, 60.65; H, 6.69; N, 8.72.
Example 73
7-Amino-1-(1-piperazinyl)-naphthalene
[0173] The product of Example 11 (7-benzamido-1-(1-piperazinyl)-naphthalene, (0.063 g, 0.19
mmol) was combined with hydrochloric acid in ethanol (4 mL) and refluxed 16 hours.
The reaction was concentrated at reduced pressure and the residue was neutralized
with 4 N sodium hydroxide and extracted with methylene chloride. The organic phase
was washed with brine, dried and concentrated to a tan solid (0.041 g). The solid
was recrystallized from ethyl acetate / hexane to give 0.020 g (47%) of the title
compound as light tan crystals. mp 184-186°C. HRMS m/e calculated for C
14H
17N
3: 227.1419. Observed m/e 227.1405.
Example 74
7-(Imidazolo-[4,5-b]-pyridin-1-yl)-1-(1-piperazinyl)-naphthalene
[0174] A two phase mixture of methylene chloride (50 mL) and water (100 mL) containing 7-amino-1-(1-piperazinyl)-naphthalene
(5.05 g, 22.23 mmol) and sodium carbonate (2.36 g, 22.23 mmol) was treated with di-tert-butyl
dicarbonate (4.85 g, 22.23 mmol, in 40 mL methylene chloride) dropwise with a 10 mL
methylene chloride rinse. The reaction was stirred overnight, then the phases were
separated. The organic layer was washed with brine, dried, concentrated onto silica
gel and flash chromatographed (1.5 x 3.5 inches). Elution proceeded as follows: 10%
ethyl acetate / hexane (700 mL), 1.62gof7-tert-butoxycarbonylamino-1-(4-tert-butoxycarbonyl-1-piperazinyl)-naphthalene
as a yellow foam; 10% ethyl acetate / hexane (200 mL) and 30% ethyl acetate / hexane
(500 mL), 4.18 g of 7-amino-1-(4-tert-butoxycarbonyl-1-piperazinyl)-naphthalene as
a brown foam which had
1H NMR δ 7.67 (d, J = 8.5 Hz, 1 H), 7.46 (d, J = 8 Hz, 1 H), 7.35 (d, J = 2.5 Hz, 1
H), 7.17 (t, J = 7.5 Hz, 1 H), 7.01 (dd, J = 1, 7.5 Hz, 1 H), 6.95 (dd, J = 2.5, 8.5
Hz, 1 H), 3.90 (br s, 2 H), 3.05 (br s, 8 H), 1.51 (s, 9 H).
[0175] A mixture of 7-amino-1-(4-tert-butoxycarbonyl-piperazinyl)-naphthalene (0.523 g,
1.60 mmol, product of the above reaction), 2-chloro-3-nitropyridine-N-oxide (0.335
g, 1.92 mmol, product of preparation 5) and 4-dimethylaminopyridine (0.195 g, 1.60
mmol) in ethanol (40 mL) was refluxed 2 hours. The solvent was removed at reduced
pressure and the residue was taken up in methylene chloride. The organic solution
was washed with saturated aqueous sodium bicarbonate and brine and the aqueous washes
were back extracted (5x) with methylene chloride. The combined organic phase was dried,
concentrated onto silica gel and flash chromatographed (1 x 3 inches). Elution proceeded
as follows: 50% ethyl acetate / hexane (200 mL) and 75% ethyl acetate / hexane (200
mL), nil; 70% ethyl acetate / hexane (100 mL) and ethyl acetate (300 mL), 0.458 g
(61%) of 7-(3-nitro-1-oxido-2-pyridylamino)-1-(4-tert-butoxycarbonyl-1-piperazinyl)-naphthalene
as a dark red foam which was suitable for use without further purification. A sample
recrystallized from ether / hexane as orange crystals had mp 191-193°C. Analysis calculated
for C
24H
27N
5O
5: C, 61.92; H, 5.85; N, 15.04. Found: C, 61.59; H, 5.79; N, 14.54.
[0176] A mixture of 7-(3-nitro-1-oxido-2-pyridylamino)-1-(4-tert-butoxycarbonyl-1-pip erazinyl)-naphthalene
(0.40 g, 0.86 mmol, product of the above reaction), ammonium formate (1.0 g, 17.2
mmol), and 10% palladium on carbon (0.15 g) in ethanol (30 mL) was refluxed 4 hour
while continually returning sublimed ammonium formate back into the reaction. The
solvent was removed at reduced pressure and the residue was taken up in methylene
chloride. The organic solution was washed with water and brine, dried over calcium
sulfate, and concentrated. The residue was flash chromatographed on silica gel (1
x 3 inches). Elution proceeded as follows: 25% ethyl acetate / hexane (100 mL), nil;
35% ethyl acetate / hexane (250 mL), 0.25 g of product. The product was treated with
activated carbon, filtered, and concentrated. The residue was recrystallized frim
ethyl acetate / ether to give 0.11 g (30%) of 7-(3-amino-2-pyridylamino)-1-(4-tert-butoxycarbonyl-1-piperazinyl)-naphthalene
as white crystals which were sensitive to air (turn brown on air exposure) and had
mp 183-184°C. Analysis calculated for C
24H
29N
5O
2: C, 68.71; H, 6.97; N, 16.69. Found: C, 68.76; H, 6.58; N, 16.56.
[0177] A mixture of 7-(3-amino-2-pyridylamino)-1-(4-tert-butoxycarbonyl-1-piperazinyl)-naphthalene
(0.124 g, 0.296 mmol, product of the above reaction) and ethoxymethylenemalononitrile
(0.47 g, 0.385 mmol) in isopropanol (7 mL) was refluxed 4 hour. Additional ethoxymethylenemalononitrile
(0.035 g) was added and the reaction was refluxed overnight. The reaction was concentrated
onto silica gel and flash chromatographed (1 x 3.5 inches). Elution proceeded as follows:
10% ethyl acetate / hexane (400 mL), nil; 20% ethyl acetate / hexane (300 mL), unweighed
isopropoxymethylenemalononitrile; 20% ethyl acetate / hexane (50 mL) and 40% ethyl
acetate / hexane (300 mL), 0.082 g (65%) of 7-(imidazolo-[4,5-b]-pyridin-1-yl)-1-(4-tert-butoxycarbonyl-1-piperazinyl)-naphthalene
as a tan oily foam which was suitable for use as obtained which had
1H NMR
δ 8.76 (d, J = 2 Hz, 1 H), 8.51-8.48 (m, 2 H), 8.20 (dd, J = 1.5, 8 Hz, 1 H), 8.04
(d, J = 9 Hz, 1 H), 7.84 (dd, J = 5, 8 Hz, 1 H). 7.65 (d, J = 8 Hz, 1 H), 7.49 (t,
J = 8 Hz, 1 H), 7.36 (dd, J = 5, 8 Hz, 1 H), 7.17 (d, J = 7.5 Hz, 1 H), 4.20-3.30
(br coelesced signal, 4 H), 3.16 (br s, 4 H), 1.51 (s, 9 H).
[0178] A solution of 7-(imidazolo-[4,5-b]-pyridin-1-yl)-1-(4-tert-butoxycarbonyl-1-pip erazinyl)-naphthalene
(0.076 g, 0.177 mmol) in ethanol (6 mL) was treated with hydrogen chloride saturated
dioxane (4 mL). The mixture was stirred 10 hours at room temperature and a fine precipitate
formed. The solvent was removed at reduced pressure and the residue was dissolved
in hot methanol and filtered. The filtrate was concentrated to about 4 mL at the boil
and treated with ethanol (3 mL). The white crystals obtained on cooling were collected
and washed with cold ethanol to give 0.022 g (33%) of the dihydrochloride of the title
compound. mp >250°C. Analysis calculated for C
20H
19N
5 2 HCI: C, 59.71; H, 5.26; N, 17.41. Found: C, 59.72; H, 5.29; N, 16.62.
Example 75
7-(1,2,3-Triazolo-[4,5-b]-pyridin-1-yl)-1-(1-piperazinyl)-naphthalene
[0179] A mixture of 7-(3-amino-2-pyridylamino)-1-(4-tert-butoxycarbonyl-1-piperazinyl)-naphthalene
(0.038 g, 0.0906 mmol, intermediate of example 74) in 5% sulfuric acid (1.5 mL, precooled
to 0°C) was treated with sodium nitrite (0.0066 g, 0.095 mmol) in water (0.1 mL) with
a water rinse (2 x 0.1 mL). The heterogeneous mixture was stirred 40 minutes at 0°C.
The reaction was diluted with ice and neutralized with 1 N sodium hydroxide. The reaction
was extracted with methylene chloride and this organic phase was washed with saturated
aqueous sodium bicarbonate and brine, dried, and concentrated to yield 7-(1,2,3-triazolo-[4,5-b]-pyridin-1-yl)-1-(4-tert-butoxycarbonyl-1-piperazinyl)-naphthalene
as a brown oil (0.034 g, 87%) which was suitable for use without purification. A sample
treated with activated carbon in methylene chloride and then recrystallized from ether
/ hexane had mp 173-175°C. Analysis calculated for C
24H
26N
6O
2: C, 66.96; H, 6.09; N, 19.52. Found: C, 66.61; H, 6.18; N, 19.28.
[0180] A solution of 7-(1,2,3-triazolo-[4,5-b]-pyridin-1-yl)-1-(4-tert-butoxycarbonyl-1-piperazinyl)-naphthalene
(0.075 g, 0.174 mmol, product of the above reaction) in ethanol (4 mL) was treated
with hydrogen chloride saturated dioxane (4 mL) and the mixture was stirred at room
temperature 10 hours. The solvent was removed at reduced pressure and the residue
was dissolved in hot methanol. The methanol solution was filtered hot and the filtrate
was concentrated at the boil to about 1 mL. Yellow crystals formed on cooling. These
crystals were collected to give 0.031 g (48%) of the hydrochloride the title compound.
mp >250°C. Analysis calculated for C
19H
18N
6 HCI: C, 62.21; H, 5.22; N, 22.91. Found: C, 62.11; H, 5.11; N, 22.53.
Example 76
1-(4-Methylpiperazin-1-yl)-7-(pyrimid-5-yl)naphthalene
[0181] A mixture of 7-trifluoromethylsulfonyloxy-1-(4-methylpiperazin-1-yl)naphthalene (0.250
g, 0.67 mmol), bis(triphenylphosphine)palladium[II] chloride (0.025 g, 0.036 mmol),
5-trimethylstannylpyrimidine (0.178 g, 0.74 mmol, from Preparation 6), triethylamine
(0.45 mL, 3.23 mmol), lithium chloride (0.088 g, 2.07 mmol), 2,6-di-
tert-butyl-4-methylphenol (approximately 0.01 g), and N,N-dimethylformamide (12.5 mL)
was heated between 100°C to 115°C under nitrogen for 45 minutes. The resulting mixture
was concentrated via evaporation under reduced pressure, and the residue was column
chromatographed using silica gel (approximately 25 g) and elution with 9:1:0.1 [methylene
chloride/methanol/ammonium hydroxide] to afford the title compound (0.060 g, 0.20
mmol, 29%) as a pale yellow foam: R
f = 0.15 in 20% methanol in ethyl acetate;
13C NMR (CDCl
3) δ 157.3, 155.0, 149.8, 134.6, 134.5, 130.8, 129.9, 129.0, 127.1, 124.0, 123.4, 122.1,
116.0, 55.4, 52.7, 45.9; LRMS (m/z, relative intensity) 304 (M
+, 7), 240 (100), 225 (15), 196 (16), 169 (44), 155 (33), 141 (16); HRMS m/e calculated
for C
19H
20N
4 304.1690. Observed m/e 304.1689.
Example 77
7-(5-Cyanopyrid-3-yl)-1-(4-methylpiperazin-1-yl)naphthalene
[0182] A mixture of 7-trifluoromethylsulfonyloxy-1-(4-methylpiperazin-1-yl)naphthalene (0.527
g, 1.53 mmol), bis(triphenylphosphine)palladium[II] chloride (0.537 g, 0.77 mmol),
5-cyano-3-trimethylstannylpyridine (0.0.450 g, 1.69 mmol, from preparation 7), triethylamine
(1.02 mL, 7.34 mmol), lithium chloride (0.194 g, 4.59 mmol), 2,6-di-tert-butyl-4-methylphenol
(approximately 0.01 g), and N,N-dimethylformamide (6 mL) was heated between 100°C
to 115°C under nitrogen for 1.5 hours. The resulting mixture was concentrated via
evaporation under reduced pressure, and the residue was column chromatographed using
silica gel (approximately 25 g) and elution with 5% methanol in ethyl acetate to afford
the title compound (0.170 g, 0.52 mmol, 34%) as a pale yellow foam: R
f = 0.40 in 5% methanol in ethyl acetate;
1H (CD
3OD) δ 9.08 (d,
J=2.2 Hz, 1H), 8.82 (d,
J=2.2 Hz, 1H), 8.43 (t,
J=2.0 Hz, 1H), 8.36 (br s, 1H), 7.92 (d,
J=8.5 Hz, 1H), 7.70 (dd,
J=1.8 and 8.5 Hz, 1 H), 7.57 (br d,
J=8.2 Hz, 1H), 7.44 (t,
J=7.8 Hz, 1H), 7.17 (d,
J=7.3 Hz, 1H), 3.20-3.00 (br s, 4H), 2.85-2.65 (br s, 4H), 2.40 (s, 3H); LRMS (m/z,
relative intensity) 328 (M
+, 100); HRMS m/e calculated for C
21H
20N
4 328.1690. Observed m/e 328.1715
Example 78
General procedure for the synthesis of (1-piperazinyl)naphthyl-7-yl ethers.
[0183] To a flame dried round bottom flask was added 7-hydroxy-1-(4-methyl-1-piperazinyl)naphthalene
(0.30 g, 1.23 mmol), anhydrous N,N-dimethylformamide (3 mL), and 60% dispersion of
sodium hydride in mineral oil (0.060 g; 1.47 mmol, 1.2 eq). The resulting suspension
was heated for twenty minutes at 40°C, and the resulting reaction mixture was then
allowed to cool to room temperature. A suspension of the appropriate alkylating agent
or appropriate electrophile (1.35 mmol, 1.1 eq), anhydrous DMF (1 mL) and 60% sodium
hydride (0.075 grams 0.00183 moles) was then added slowly over 30 minutes in three
portions to the reaction mixture, and the resulting mixture was heated at 80°C. The
progress of the reaction was monitored by TLC, and reaction completion was determined
by consumption of 7-hydroxy-1-(4-methyl-1-piperazinyl)naphthalene as determined by
TLC. Upon determination of reaction completion, DMF was then removed
in vacuo, and the residue was partitioned between methylene chloride (40 mL) and saturated
sodium bicarbonate solution (40 mL). The organic layer was removed, dried (Na
2SO
4), and concentrated
in vacuo. The resulting residue was purified by flash column chromatography using silica gel
(15 grams) and elution with 12:1:0.04 [CH
2Cl
2: methanol: NH
4OH] to afford the title compound. Using the above general procedure, the following
compounds were prepared:
A. 2-[8-(Methylpiperazin-1-yl)napthalen-2-yloxy]nicotinonitrile
[0184] 2-Chloro-3-cyanopyridine was the electrophile. Chromatography afforded the title
compound (33%) as an amorphous solid: HRMS m/e calculated for C
21H
20N
4O 344.1637. Observed m/e 344.1618;
13C NMR (CDCl
3) δ 46.2, 52.9, 55.6, 97.7, 114.6, 115.0, 115.7, 118.1, 121.1, 123.4, 125.8, 129.9,
130.1, 132.7, 143.5, 149.6, 150.0, 151.5, 163.9.
Example 79
8-(4-Methylpiperazin-1-yl)naphthalene-2-carboxylic acid phenylamide
[0185] To a flame dried 3-neck flask were added 7-trifluoromethylsulfonyloxy-1-(4-methylpiperazin-1-yl)naphthalen
e (0.95g, 2.54 mmol), aniline (0.35 mL, 3.81 mmol), and triethylamine (0.39 mL, 2.79
mmol). A balloon of carbon monoxide provided a CO atmosphere above the reaction mixture
via the reflux condenser. The reaction contents were heated at 100°C for ten minutes.
The solution was then cooled to 70°C, and bis(triphenylphosphine)palladium(II) chloride
(0.036 g, .05 mmol, 2 mol%) was added to the reaction solution. The resulting reaction
mixture was stirred at 100°C for 19 hours. Then the CO balloon was refilled with CO,
additional triethylamine (approx. 0.5 mL) was added, and this mixture was stirred
at 100°C for 5 hours. Ethyl acetate (25 mL) was added to the cooled reaction mixture,
and this mixture was then filtered through Celite®. The filtrate was concentrated
in vacuo. The residue was purified using flash column chromatography using silica gel (30 g)
and elution with 5% methanol in ethyl acetate to afford the title compound (0.090
g, 10%) as an amorphous solid: R
f = 0.42 in 9:1:0.1 methylene chloride/methanol/ammonium hydroxide; HRMS m/e calculated
for C
22H
23N
3O 345.1843. Observed m/e 345.1873;
13C NMR (CDCl
3) δ 46.0, 52.9, 55.4, 115.9, 120.3, 123.2, 123.3, 123.7, 124.6, 128.0, 128.1; 129.1,
131.5, 136.2, 138.1, 150.5, 167.0.
Example 80
8-(4-Methylpiperazin-1-yl)naphthalene-2-carboxylic acid 4-chlorobenzylamide
[0186] A mixture of 7-trifluoromethylsulfonyloxy-1-(4-methylpiperazin-1-yl)naphthalene (9.0
g, 24 mmol), bis (triphenylphosphine) palladium chloride (0.36 g, 0.51 mmol) and methanol
(90 mL) was warmed to 60°C under a balloon of carbon monoxide for 96 hours. The reaction
was cooled to room temperature and charged with additional catalyst (0.28g, 0.396
mmol). The mixture was again placed under a carbon monoxide atmosphere and refluxed
40 hours. The reaction was cooled filtered and concentrated to a brown oil. This residue
was flash chromatographed on silica gel (300 g). Elution was 30: 1: 0.03 ethyl acetate,
methanol, ammonium hydroxide to afford 2.7 g (39.5%) of methyl 8-(4-methylpiperazin-1-yl)naphthalene-2-carboxylate
as a light yellow solid: tlc: R
f = 0.32 (10: 0.5: 0.05, ethyl acetate, methanol, ammonium hydroxide),
13C NMR δ 167.36, 150.32, 136.85, 128.64, 128.39, 127.83, 126.58, 125.89, 125.19, 123.37,
115.57, 55.22, 52.33, 52.17, 45.54, HRMS m/e calculated for C
17H
20N
2O
2: 284.152. Observed m/e: 284.1513.
[0187] A mixture of the above ester (1.56 g, 5.48 mmol), methanol (50 mL) and lithium hydroxide
(1.15 g, 27.4 mmol) was refluxed 22 hours. The reaction was concentrated and the residual
solid was treated with hydrochloric acid in dioxane (32.9 mL, 32.9 mmol, 1N). Water
(3 mL) was added to yield a clear solution which was concentrated in vacuo to afford
8-(4-methylpiperazin-1-yl)naphthalene-2-carboxylic acid hydrochloride as a solid which
also contained lithium hydrochloride. This material was used without purification
and assumed to be a quantitative yield reaction. HRMS m/e calculated for C
16H
18N
2O
2: 270.1370. Observed m/e: 270.1360.
[0188] A mixture of the above acid (0.25 g, 0.82 mmol), methylene chloride (4 mL), N-methylmorpholine
(0.31 mL, 2.87 mmol), 1-hydroxy benzotriazole hydrate (0.12 g, 0.9 mmol), 4-chlorobenzylamine
(0.1 mL, 0.82 mmol) and 1-cyclohexyl-3-(7-morpholinoethyl) carbodiimide p-toluenesulfonate
(0.69 g, 1.62 mmol) was stirred 17 hours at ambient temperature. The reaction was
diluted with water (10 mL) and methylene chloride (10 mL) and adjusted to pH 9 by
addition of saturated aqueous sodium carbonate. The phases were separated and the
organic layer was dried over sodium sulfate and concentrated to a yellow solid. This
material was purified by flash chromatography on silicon gel (6 g). Elution with 12:
1: 0.04, methylene chloride, methanol, ammonium hydroxide gave 0.07 g (21.8%) of the
title compound as a solid: mp 72-74°C; tlc: R
f = 0.28 (12: 1: 0.04, methylene chloride, methanol, ammonium hydroxide);
13C NMR δ 168.04, 150.69, 137.09, 136.16, 133.17, 130.82, 129.01, 128.90, 128.77, 128.18,
127.91, 123.84, 123.30, 123.07, 115.61, 55.47, 53.10, 46.13, 43.34. HRMS m/e calculated
for C
23H
24ClN
3O: 393.1607. Observed m/e: 393.1642.
Example 81
7-(3-Methoxyphenyl)-1-(4-methylpiperazin-1-yl)naphthalene
[0189] A mixture of 3-methoxy-1-bromobenzene (0.089 mL, 0.71 mmol), 7-trimethylstannyl-1-(4-methylpiperazin-1-yl)naphthalene
(0.25 g, 0.64 mmol), bis-(acetonitrile) palladium chloride (0.0085 g, 0.032 mmol),
tri(3-methoxyphenyl)phosphine (0.023 g, 0.064 mmol), and butylated hydroxytoluene
(BHT, about 0.001 g, antioxidant) in dimethyl formamide (12 mL) was warned to 110°C
for 2 hours. The reaction was cooled to room temperature and diluted with 1 N aqueous
lithium chloride (25 mL) and 1 N sodium hydroxide (2 mL); then extracted with ether
(3X). The combined ether layer was washed with 1 N aqueous lithium chloride and brine.
The organic phase was dried over calcium sulfate and concentrated. The residue was
purified by flash chromatography on silica gel (1x2.5 inches). Elution proceeded as
follows: 75% ethyl acetate / hexane, 200 mL, nil; 2% methanol / ethyl acetate 200
mL and 10% methanol / ethyl acetate, 200 mL, 0.084 g of an oil. This oil was further
purified by kugelrohr distillation (1 mm Hg). The distillation proceeded as follows:
110-130°C, 0.014 g of a mixture of the title product and 7-methyl-1-(4-methylpiperazin-1-yl)naphthalene:
200-220°C, 0.062 g (23%) of the title compound as a yellow oil:
1H NMR δ 8.43 (incompletely resolved dd, J = 1.2Hz, 1 h), 7.90 (d, J = 9 Hz, 1 H),
7.74 (dd, J = 2, 8.5 Hz, 1 H), 7.58 (d, J = 8 Hz, 1 H), 7.43 (sym m, 2 H), 7.34 (dt,
J = 1.5, 7.5 Hz, 1 H), 7.29 (5, J = 2 Hz, 1 H), 7.14 (dd, J = 1, 7.5 Hz, 1 H), 6.96
(ddd, J = 1, 2.5, 8 Hz, 1H), 3.92 (s, 3 H) 3.20 (br s, 4 H), 2.75 (br s, 4 H), 2.44
(s, 3 H). The product was dissolved in chloroform and HCL gas was bubbled through
the solution to form the hydrochloride salt. Concentration of this solution to about
1 mL. at the boil and addition of about 1 mL of ether caused the white crystalline
product to precipitate. The hydrochloride salt weighted 0.057 g: mp 236-238°C. Analysis
calculated for C
22H
24N
2O • HCl: C, 71.63; H, 6.83; N, 7.59. Found: C, 71.31; H, 6.92; N, 7.59.
Example 82
1-(1-Methylpiperidin-4-yl)-7-naphthalene carboxylic acid 4-chlorobenzylamide
[0190] A mixture of 1-(1-methylpiperidin4-yl)-7-trifluoromethylsulfonyloxynaphthalene (1.0
g, 2.69 mmol), 4-chlorobenzylamine (0.59 mL, 4.84 mmol) and bis (triphenylphosphine)palladium
chloride (0.095 g, 0.13 mmol), and triethylamine (0.56 mL, 4.04 mmol) was blanketed
with an atmosphere of carbon monoxide (with the aid of a balloon) and heated to 110-120°C
for 2 hours. Additional 4-chlorobenzylamine (0.2 mL) was added and the reaction was
heated under carbon monoxide for 17 hours more. The reaction was cooled to room temperature
and taken up in ethyl acetate. The mixture was extracted with water and brine, dried
over calcium sulfate, and concentrated. The residue was flash chromatographed on silica
gel (1.5 x 2.5 inches). Elution proceeded as follows: ethyl acetate, 350 mL, nil;
2% methanol / ethyl acetate, 300 mL, nil; 4% methanol / 1% triethylamine / ethyl acetate,
200 mL, 0.085 g of impure product. Continued elution with 4% methanol / 1% triethylamine
/ ethyl acetate, 200 mL, 0.266 g (25%) of the title compound as a yellow oil.
1H NMR (DMSO
d6) δ 8.74 (s, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.73 (dt, J=1.5, 8.5 Hz, 2H), 7.58-7.48
(m, 2H), 7.35 (s, 4H), 6.63 (br t, J=6 Hz, 1H), 4.70 (d, J=6 Hz, 2H), 3.42 (quintuplet,
J=8 Hz, 1H), 3.05 (br d, J=12 Hz, 2H), 2.38 (s, 3H), 2.23 (sym m, 2H), 1.99-1.92 (m,
4H). HRMS m/e calculated for C
24H
25C1N
2O: 393.1733. Observed m/e: 393.1747.
[0191] Synthesis of intermediates used in the above Examples are described in the preparations
below.
Preparation 1
7-hydroxy-1-(4-methyl-1-piperazinyl)-3,4-dihydronaphthalene
[0192] 7-Hydroxy-α-tetralone (1.0 g, 6.17 mmol, Corey and Estreicher, Tetrahedron Lett.,
1981, 22, 603) and 1-methylpiperazine (2.2 mL, 19.83 mmol) were dissolved in dry THF (90
mL) and chilled to 0°C. Titanium tetrachloride (0.91 mL, 8.3 mmol) was allowed to
run down the side of the reaction vessel into the reaction via syringe to give a vigorous
reaction which caused the solution to turn orange-red. The mixture was allowed to
warm to ambient temperature and stir 1.5 hours. A 2:1 mixture of water and concentrated
ammonium hydroxide (90 mL) was added and the mixture was extracted with ethyl acetate.
The organic phase was dried over calcium sulfate and concentrated to give 1.48 g of
crude enamine which was used immediately without characterization. (This enamine was
not stable to chromatography but did show a characteristic signal in the
1H NMR for the enamine vinyl proton at 5.28 ppm with a 4.7 Hz coupling constant).
Preparation 2
7-Hydroxy-1-(4-methyl-1-piperazinyl)-naphthalene
[0193] 10% Palladium on carbon (1.16 g) and 7-hydroxy-1-(4-methyl-1-piperazinyl)-2,3-dihydronaphthalene
(1.48 g, 6.06 mmol) were slurried in toluene (100 mL) and refluxed 16.5 h. The mixture
was cooled, filtered, and concentrated. The product was purified by flash chromatography
on silica gel (1 x 6 inches). Elution with 50 % ethyl acetate/hexane followed by 100%
ethyl acetate gave 0.51 g (34%) of the title product as a light pink foam. A sample
was recrystallized from ether to give a cream colored solid for analysis: mp 184-185°C.
Analysis calculated for C
15H
18N
2O: C, 74.35; H, 7.49; N, 11.56. Found: C, 74.05; H, 7.03; N, 11.42.
Preparation 3
7-Trimethylstannyl-1-(4-methyl-1-piperazinyl)-naphthalene
[0194] 7-trifluoromethylsulfonyloxy-1-(4-methyl-1-piperazinyl)-naphthalene (2.0 g, 5.34
mmol), hexamethylditin (1.92 g, 5.86 mmol), lithium chloride (0.68 g, 16 mmol), tetra
(triphenylphosphine) palladium (0.24 g, 0.21 mmol) and butylated hydroxytoluene (a
few crystals, antioxidant) were combined in dry dioxane (50 mL) and refluxed 45 minutes.
The mixture was cooled and quenched with saturated ammonium chloride (50 mL). The
mixture was extracted with ether (2x) and the combined organic phase was washed with
brine, dried over magnesium sulfate, and concentrated to a brown oil. Flash chromatography
on silica gel (2 x 4 inches) with 50% ethyl acetate/hexane elution gave 0.77 g (37%)
of the title product as a light brown oil which slowly solidified. The product was
suitable for use in subsequent reactions but was not analytically pure: 'H NMR δ 8.36
(s with Sn coupling, 1H), 7.80 (d,
J = 8 Hz, 1H), 7.61-7.51 (m, 2H), 7.40 (t,
J = 8 Hz, 1H), 7.09 (dd,
J = 1, 7.5 Hz, 1H), 3.2 (br s, 4H), 2.75 (br s, 4H), 2.46 (s, 3H), 0.39 (s with Sn
coupling of 55.0 and 52.5 Hz, 9H).
Preparation 4
8-Bromo-2-(dibenzylamino)-naphthalene
[0195] A mixture of dibenzylamine (70.8 mL, 0.368 mol), 8-bromo-2-tetralone (82.86 g, 0.368
mol, U. S. patent 4,897,405 A), dry toluene (1000 mL), and p-toluenesulfonic acid
(0.83 g, 4.36 mmol) was refluxed 2 days with azeotropic removal of water. Most of
the toluene was distilled away from the reaction and the residual material was dried
in vacuo about 12 hours. The crude enamine was obtained as an orange oil and was used
directly in the next step.
1H NMR δ 7.41-7.17 (m, 13 H), 6.97 (d, J = 7.3 Hz, 1 H), 6.72 (t, J = 7.6 Hz, 1 H),
5.83 (s, 1 H), 4.54 (s, 4 H), 2.86 (t, J = 7.8 Hz, 2 H), 2.55 (dd, J = 8.5, 6.6 Hz,
2 H).
[0196] The enamine from the above reaction was dissolved in tetrahydrofuran (2000 mL) and
chilled to 0°C. Chloranil (90.48 g, 0.368 mol) was added in portions over 10 minutes.
The black solution was stirred 1.45 hours at 0°C, then the solvent was removed at
reduced pressure. The residue was taken up in methylene chloride (750 mL) and filtered
through celite to remove an insoluble yellow material (discarded). Saturated sodium
carbonate (500 mL) was added to the filtrate and the two phase mixture was vigorously
stirred 15 minutes. The mixture was again filtered through celite to remove a greenish
solid (discarded). The phases were separated from the filtrate and the organic layer
was washed with saturated sodium carbonate and then brine. The solution was dried
over calcium sulfate and concentrated onto silica gel and applied to a flash chromatography
column (4 x 4 inches silica gel). Elution proceeded as follows: hexane (500 mL, nil);
5% ether / hexane (2 L, nil); 5% ether / hexane (12 L, unweighed orange oil product).
The oil was triturated with 50% ether:hexane (500 mL) to yield the tan product, 8-bromo-2-(dibenzylamino)-naphthalene
(72.15 g). The residues from the trituration were rechromatographed as above to afford
an additional 18.95 g of product. The combined yield was 91.1 g, 61%. mp 102.5-103°C;
1H NMR δ 7.64-7.50 (m, 3 H), 7.37-7.24 (m, 11 H), 7.13 (dd, J = 9, 2.5 Hz, 1 H), 7.00
(t, J = 7.8 Hz, 1 H), 4.80 (s, 4 H). Analysis calculated for C
24H
20BrN: C, 71.65; H, 5.01; N, 3.48. Found: C, 71.24; H, 4.65; N, 3.49.
Preparation 5
2-Chloro-3-nitropyridine-N-oxide
[0197] 2-Chloro-3-nitropyridine (0.69 g, 4.35 mmol) was chilled to 0°C and trifluoroacetic
acid (9 mL) was slowly added followed by 30% hydrogen peroxide (1 mL). The solution
was warmed to 70°C for 1.5 hours, cooled to 0°C and excess peroxide was decomposed
by dropwise addition of dimethylsulfide (1 mL) and stirring 0.5 hours. The reaction
was concentrated at reduced pressure onto silica gel and flash chromatographed (1
x 3 inches). Elution proceeded as follows: 50% ethyl acetate / hexane (175 mL), nil;
75% ethyl acetate / hexane (175 mL), 0.589 g (77%) of 2-chloro-3-nitropyridine-N-oxide
as an orange solid suitable for use without further purification. A sample recrystallized
from ethyl acetate / hexane had mp 98-100°C. Analysis calculated for C
5H
3ClN
2O
3: C, 34.41; H, 1.73; N, 16.05. Found: C, 34.75; H, 1.67; N, 15.80.
Preparation 6
5-Trimethylstannylpyrimidine
[0198] A mixture of 5-bromopyrimidine (4.00 g, 25.16 mmol), hexamethylditin (9.06 g, 27.67
mmol), lithium chloride (1.27 g, 30.19 mmol), tetrakis(triphenylphosphine) palladium
(1.13 g, 0.981 mmol), 2,6-di-
tert-butyl-4-methylphenol (approximately 0.01 g), and dioxane (45 mL) was heated at reflux
under nitrogen for 7 hours. The resulting mixture was concentrated via evaporation
under reduced pressure, and the residue was column chromatographed using silica gel
(approximately 200 g) and elution with ethyl acetate/hexanes [1:1] to afford the title
compound (4.75 g, 19.6 mmol, 78%) as a clear, colorless liquid: R
f = 0.6 in ethyl acetate/hexanes [1:1];
1H NMR (CDCl
3) δ 9.11 (s, 1H), 8.70 (s, 2H), 0.38 (s, 9H);
13C NMR (CDCl
3) δ 162.8, 158.5, 134.4, -9.6.
Preparation 7
5-Cyano-3-trimethylstannylpyridine
[0199] A mixture of 3-bromo-5-cyanopyridine (5.84 g, 31.91 mmol), hexamethylditin (11.49
g, 35.10 mmol), lithium chloride (1.62 g, 38.29 mmol), tetrakis(triphenylphosphine)palladium
(1.44 g, 1.24 mmol), 2,6-di-
tert-butyl-4-methylphenol (approximately 0.01 g), and dioxane (60 mL)was heated at reflux
under nitrogen for 8 hours. The resulting mixture was concentrated via evaporation
under reduced pressure, and the residue was column chromatographed using silica gel
(approximately 200 g) and elution with ether/hexanes [1:1] to afford the title compound
(1.98 g, 7.41 mmol, 23%) as a pale yellow solid: mp, 77.0-79.0°C; R
f = 0.65 in ether/hexanes [1:1];
1H NMR (CDCl
3) δ 8.80 (dd,
J=1.5 and 2.4 Hz, 2H), 8.03 (dd,
J=1.5 and 2.1 Hz, 1H), 0.39 (s, 9H).
[0200] The compounds of formula I of the present invention described in the above Examples
were assayed for 5-HT
1A and 5-HT
1D affinity using the aforementioned procedures with IC
50s of less than 0.60
µM for at least one of the above affinities.